bims-glucam 2026-10-25 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–10–25
28 papers selected by
Sreeparna Banerjee, Middle East Technical University

Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
NUAK isoforms promote glucose and glutamine metabolic reprogramming driven colon cancer progression and migration through regulation of AMPK/mTOR signaling.
Targeting SLC1A5-mediated glutamine metabolism overcomes PARP inhibitor resistance in ovarian cancer.
Lung cancer metabolism: a dynamic and adaptive network.
Rare-Earth-Coordinated Glutamine Nanostructure-Induced "Pseudo-Overnutrition" Metabolic Therapy.
Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.
Discovery of Novel Glutaminase (GLS1) and Histone Deacetylase (HDAC) Dual Inhibitors as a Promising Strategy for Cancer Therapy.
In Cellulo Observation of De Novo-Synthesized Nucleotide by Spectral Tracing of Glutamine-Derived Nitrogen Metabolism (QN-STIM) in Cancer Cells.
Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.
The tumor macroenvironment as cancer metabolism's next frontier.
Base editing-mediated exon-specific knockout of glutamine synthetase generates a high-productivity CHO cell line for antibody manufacturing.
From metabolic starvation to precision therapy: engineering amino acid-targeted tumor therapeutics.
Global Analysis of Metabolic Fluxes of Glucose and Glutamine in INS‑1 Cells Exposed to Arsenite Using 13C‑Isotopic Tracers.
Silver Ion-Regulated Luminescence of Chiral Au-Cysteine Nanoflowers for Highly Effective Enantioselective Recognition of Glutamine.
Dysregulated PIKfyve-dependent inhibition of ClC-7 causes ammonium-dependent endolysosomal vacuolization and autophagic flux impairment: Rescue by glutaminase inhibition.
Advancing osteosarcoma treatment: the impact of intratumoral metabolic reprogramming on immunotherapy.
Metabolic processes and microenvironmental regulation in leukemia.
Hybrid lesions of hepatocellular adenoma and focal nodular hyperplasia: a clinicopathological and molecular study of two cases.
Prepregnancy Exposure to High Doses of Nanoplastics Triggers Persistent Vaginal Microbiome Dysbiosis to Induce Adverse Pregnant Outcomes.
Gentiopicroside protects against kainic acid-induced excitotoxicity by preserving glutamate homeostasis in rats.
Reduced hepatic GLUL expression accompanies altered RIP3/MLKL-pathway protein abundance in early cholestatic liver injury following bile duct ligation.
Glucocorticoids in breast cancer: physiologic mechanisms and relationship to risk, survival, and treatment response.
[L-lactylation regulatory network in orthopedic degenerative diseases].
hnRNPC promotes oral squamous cell carcinoma progression via N6-methyladenosine-dependent stabilization of BCAT1 to enhance branched-chain amino acid metabolism.
Hyperosmotic stress in renal tubular epithelial cells promotes TFEB-dependent autophagy in interstitial fibroblasts by involving extracellular glutamate.
Deubiquitination of WBP11 governs OPLAH-mediated glutathione biosynthesis to suppress triple programmed cell death in prostate cancer.
Citrullinated histone H3 and elevated polyamine metabolism gene expression in peripheral blood polymorphonuclear leukocytes as biomarkers for poor immunotherapy response in cancer patients.
Structure bioinformatics of eight human ATP synthase F0 subunits and their AlphaFold3-predicted reduced-hydrophobicity QTY analogues.

Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123

Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.

Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.

  When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.

Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA

DOI:  https://doi.org/10.1073/pnas.2613074123
J Mol Med (Berl). 2026 Oct 20. pii: 122. [Epub ahead of print]104(1):

NUAK isoforms promote glucose and glutamine metabolic reprogramming driven colon cancer progression and migration through regulation of AMPK/mTOR signaling.

Acily Skadon Worral Wilfred Raj, Jaithanya Yesupogu Moorthy Babu, Rajalakshmi Sabanayagam, Sridhar Muthusami, Ravi Manoharan.

  Colorectal cancer (CRC) cells undergo significant alterations in glucose and glutamine metabolism to support rapid growth and migration. However, the molecular mechanisms underlying these metabolic changes remain incompletely understood. Although NUAK1 and NUAK2, members of the NUAK kinase family have been implicated in CRC tumorigenesis, their specific roles in metabolic reprogramming that drives CRC progression and metastasis have not been elucidated. In this study, we demonstrate that NUAK1 and NUAK2 are overexpressed in human CRC tissues and that their expression is associated with increased tumor metastasis and poorer patient survival. NUAK1/2 promotes CRC cell proliferation and migration, whereas their depletion markedly reduces cell growth and migratory capacity. Furthermore, knockout of NUAK1/2 disrupts key metabolic pathways, including aerobic glycolysis, pentose phosphate pathway (PPP), and glutamine metabolism. Mechanistically, NUAK1/2 facilitates mTOR-driven metabolic reprogramming and promotes CRC growth and migration by suppressing AMPK activity. Depletion of NUAK1/2 impairs metabolic function, cellular growth, and migration potential in CRC cells, effects that are further enhanced by pharmacological activation of AMPK with AICAR and inhibition of mTOR using Rapamycin. In conclusion, these findings identify NUAK1/2 as critical regulators of CRC progression and migration through AMPK/mTOR-mediated metabolic reprogramming, highlighting their potential as therapeutic targets in colorectal cancer.

Keywords:  AMPK/mTOR signalling; Colorectal cancer; Glucose and glutamine metabolic reprogramming; NUAK1/2

DOI:  https://doi.org/10.1007/s00109-026-02730-5
Cell Death Dis. 2026 Jul 22. pii: 890. [Epub ahead of print]17(1):

Targeting SLC1A5-mediated glutamine metabolism overcomes PARP inhibitor resistance in ovarian cancer.

Fang Han, Hongjie Du, Kunlin Tian, Gonghua Qi, Beihua Kong, Xia Luo, Hanlin Ma.

Poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib, have significantly improved outcomes in ovarian cancer (OC); however, therapy resistance remains a major clinical challenge. Here, we showed that glutamine metabolism was upregulated in PARPi-resistant OC cells and identified the glutamine transporter SLC1A5 as a key mediator of this metabolic adaptation. Inhibition of SLC1A5 increased the sensitivity of OC cells to olaparib both in vitro and in vivo. Mechanistically, we demonstrated that the deubiquitinating enzyme USP14 directly interacted with and stabilized SLC1A5 by removing K48-linked polyubiquitin chains, thereby enhancing glutamine uptake, promoting glutathione synthesis, alleviating oxidative stress, and activating the mTORC1 pathway. This metabolic rewiring improved DNA damage repair capacity and ultimately contributed to PARPi resistance. Notably, combined treatment with the SLC1A5 inhibitor V-9302 and olaparib synergistically suppressed tumor growth in a patient-derived xenograft (PDX) model. Collectively, our findings identify the USP14-SLC1A5 axis as a novel regulator of PARPi resistance and suggest that targeting glutamine metabolism represents a promising therapeutic strategy to overcome PARPi resistance in ovarian cancer.

DOI: https://doi.org/10.1038/s41419-026-09123-z
Cell Mol Life Sci. 2026 Oct 19. pii: 389. [Epub ahead of print]83(1):

Lung cancer metabolism: a dynamic and adaptive network.

Sara Gholamhosseinian-Najjar, Christian Frezza.

  Lung cancer remains the leading cause of cancer-related mortality worldwide. Although substantial progress has been made in defining the genetic, epigenetic, and molecular drivers of this heterogeneous disease, metabolic reprogramming has only recently emerged as a major determinant of tumour progression and therapeutic response. Cumulative evidence demonstrates that rather than relying on a single nutrient source or pathway, cancer cells integrate glucose and glutamine, fatty acid and one-carbon metabolism, as well as nucleotide biosynthesis, and redox-supporting circuits in a highly context-dependent manner. These programs vary across histological and molecular subtypes, reflecting the influence of lineage identity and oncogenic state on metabolic organisation. In both non-small cell lung cancer and small cell lung cancer, subtype-specific constraints shape distinct metabolic states, yet a common feature is the ability to rapidly shift between alternative nutrients and biosynthetic routes. This adaptability supports continued growth under nutrient limitation, maintains redox homeostasis, and contributes to resistance against conventional and targeted therapies. By summarising current mechanistic evidence, this review presents lung cancer metabolism as an integrated and adaptable system rather than a collection of isolated pathways, and identifies metabolic dependencies that may be leveraged for therapeutic intervention.

Keywords:  Glucose metabolism; Glutamine metabolism; Lung cancer metabolism; Metabolic plasticity; Nucleotide metabolism; Sulphur metabolism.

DOI:  https://doi.org/10.1007/s00018-026-06417-5
J Am Chem Soc. 2026 Oct 14. 148(40): 43545-43565

Rare-Earth-Coordinated Glutamine Nanostructure-Induced "Pseudo-Overnutrition" Metabolic Therapy.

Junrong Wang, Mengqian Xu, Guoqing Zhu, Shanshan Zhang, Yunlong Li, Ping'an Ma, Jun Lin, Chunxia Li.

Tumor cells display a strong dependency on nutrients, yet nutrient-deprivation strategies often fail due to their metabolic plasticity and compensatory mechanisms, and can even promote invasion and metastasis. Here, we propose a metabolic therapeutic strategy that leverages rather than suppresses tumor nutrient addiction, termed "pseudo-overnutrition". This approach induces tumor cells to continuously uptake nutrient analogs that cannot be effectively utilized, thereby decoupling nutrient input from nutrient utilization and triggering metabolic collapse. To validate this concept, we designed and assembled rare-earth-coordinated glutamine nanoparticles (RE-Gln). RE-Gln preferentially interacts with glutamine transporters on tumor-cell membranes, is subsequently internalized predominantly through macropinocytosis, and accumulates within lysosomes. The progressive accumulation of RE-Gln disrupts V-ATPase-dependent lysosomal nutrient sensing and blocks mTORC1 activation, rendering cells unable to effectively utilize nutrients despite continuous uptake. Importantly, the resulting dysfunction is confined primarily to lysosomes, while mitochondrial integrity remains preserved. This lysosome-centered impairment ultimately causes widespread disruption of glutamine and glucose metabolism. Moreover, the high-glutamine microenvironment induced by RE-Gln impairs lysosomal biogenesis and function in dendritic cells, enhancing antigen presentation and activating antitumor immunity. These findings establish "pseudo-overnutrition" as a previously unrecognized concept for metabolic intervention in cancer and provide a mechanistic framework for converting tumor nutrient dependency into a therapeutic vulnerability.

DOI: https://doi.org/10.1021/jacs.6c13842
Int J Biol Sci. 2026 ;22(15): 8302-8317

Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.

Liujiazi Shao, Chao Quan, Tao Dong, Yuchen Chen, Xin Yu, Wenlu Ouyang, Dan Qi, Jeffrey Chu, Erxi Wu, Zequan Yang, Jianjie Ma, Yongqing Li.

  Sepsis is a life-threatening inflammatory disorder characterized by immune dysregulation and organ failure, and while peptidylarginine deiminase-2 (PAD2) regulates immune responses via citrullination, its role in immunometabolism remains unclear. Here we identify a PAD2-dependent mechanism that impairs mitochondrial glutamine metabolism and macrophage polarization during sepsis. Through single-cell RNA sequencing of bronchoalveolar lavage fluid from septic mice, we found that Pad2 -/- promotes M2 macrophage polarization, reduces lung injury, and improves survival. Using mass spectrometry-based citrullinomics, we identified voltage-dependent anion channel-3 (VDAC3) as a PAD2 substrate, and further demonstrated that PAD2-mediated citrullination at residue R252 suppresses glutamine transport and α-ketoglutarate (α-KG) production, thereby impairing oxidative phosphorylation (OXPHOS) and M2 reprogramming. Notably, substitution of R252 with alanine recapitulated Pad2 -/-phenotypes, and consistent with this, Pad2 -/- mice exhibited enhanced OXPHOS, attenuated inflammation, and improved outcomes in a Pseudomonas aeruginosa-induced model of sepsis and lung injury. Collectively, these findings establish the PAD2-VDAC3-glutamine axis as a key immunometabolic checkpoint that links post-translational modification to mitochondrial metabolism and macrophage function, suggesting that targeting this pathway may offer a promising strategy to restore immune balance in sepsis.

Keywords:  M2 macrophage polarization; Pad2 knockout; VDAC3; glutamine; α-ketoglutarate

DOI:  https://doi.org/10.7150/ijbs.126368
J Med Chem. 2026 Oct 08. 69(19): 22138-22161

Discovery of Novel Glutaminase (GLS1) and Histone Deacetylase (HDAC) Dual Inhibitors as a Promising Strategy for Cancer Therapy.

Zhisheng Zhang, Xuan Zhang, Yinan Jiang, Manqi Zhang, Juan Zhao, Tianxin Li, Jiani Yang, Shengnan Shi, Xueling Cao, Lingxiang Jiang, Zihan Tian, Yongsheng Wu, Jiawen Ru, Liuxiang Zhu, Qianming Du, Jinlei Bian, Zhiyu Li, Xi Xu, Jubo Wang.

  Glutaminase 1 (GLS1) and histone deacetylases (HDACs) are important targets involved in cancer metabolism and epigenetic regulation, respectively. Herein, we report the design, synthesis, and biological evaluation of first-in-class GLS1/HDAC dual inhibitors as a single-molecule strategy for cancer therapy. Through systematic structure-activity relationship studies and biochemical profiling, compound 58 was identified as a promising dual inhibitor with moderate GLS1 inhibition and potent HDAC activity, particularly against HDAC6. Compound 58 exhibited strong antiproliferative activity in multiple cancer cell lines and modulated GLS1-associated glutamine metabolism and HDAC-related acetylation markers in cells. In a CT26 tumor-bearing mouse model, compound 58 achieved a tumor growth inhibition (TGI) rate of 91.10% without obvious systemic toxicity. Overall, this study supports GLS1/HDAC dual inhibition as a promising anticancer strategy and provides compound 58 as a valuable lead for further optimization.

Keywords:  GLS1; HDAC; antitumor; dual-target inhibitors

DOI:  https://doi.org/10.1021/acs.jmedchem.6c01288
Anal Chem. 2026 Sep 29. 98(38): 28330-28336

In Cellulo Observation of De Novo-Synthesized Nucleotide by Spectral Tracing of Glutamine-Derived Nitrogen Metabolism (QN-STIM) in Cancer Cells.

Jiro Karlo, Surya Pratap Singh.

De novo nucleotide biosynthesis is directly linked to glutamine-derived nitrogen metabolism in mammalian cells. It is a fundamental process tightly tied to cellular growth, proliferation, and metabolic reprogramming, particularly in cancer cells. Direct detection and imaging of glutamine-derived nitrogen metabolism at single-cell resolution remains a challenge. The conventional liquid chromatography-mass spectrometry-based approach for detecting de novo-synthesized nucleotide studies is mostly performed on metabolites extracted from a group of cells, which makes it inherently destructive. Herein, we introduce a vibrational spectroscopy-based single-cell metabolic detection and imaging framework, "glutamine (Q)-derived nitrogen spectral tracing and imaging (QN-STIM)". Using this strategy, we detected and mapped nitrogen flow from glutamine to de novo-synthesized nascent nucleotides at the single-cell level. First, a proof-of-concept analysis was conducted in human embryonic kidney HEK293T cells and demonstrated the feasibility of this approach in cancer cells, namely human lung carcinoma A549, human glioblastoma U87 MG, and mouse hepatoma Hepa1-6. QN-STIM technique holds immense potential to be an adjunct tool to advance our understanding of nucleotide dynamics during differentiation, stress adaptation, and immune activation, and to evaluate responses to metabolic drugs in cellulo.

DOI: https://doi.org/10.1021/acs.analchem.6c03877
Cell Death Discov. 2026 Aug 27. pii: 420. [Epub ahead of print]12(1):

Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.

Bing Zhao, Qingwei Meng, Jun Zhou, Kun He, Hekang Ding, Jing Wang, Hailiang Hu, Lingfan Xu.

Cancer cell dormancy presents a major obstacle to curative therapy, particularly in metastatic prostate cancer. Although the initial efficacy of hormonal therapy is satisfying, tumors will inevitably develop resistance. Dormant tumor cells may act as the initial source for the tumor recurrence, but the underlying mechanism remains largely unknown. Here we report that the glutamine synthesis pathway is required for cellular dormancy under androgen-deprived conditions. The key enzyme, glutamine synthetase (encoded by glutamate-ammonia ligase, GLUL), is upregulated during hormonal therapy, which leads to overabundant glutamine as a nutrient and an energy storage for tumor recurrence. The negative modulation of androgen receptor (AR) on GLUL enables activation of glutamine anabolism when AR is inhibited. Pharmacologically inhibiting GS's activity along with hormonal therapy results in cell apoptosis instead of dormancy, which significantly delays the progression of tumors into advanced PCa. In summary, we provide a novel perspective of how hormonal therapy eventually fails and highlight a combination treatment strategy to overcome therapeutic resistance of current hormonal therapy.

DOI: https://doi.org/10.1038/s41420-026-03282-w
Trends Cancer. 2026 Oct 20. pii: S2405-8033(26)00218-9. [Epub ahead of print]

The tumor macroenvironment as cancer metabolism's next frontier.

Allison B Grenell, Joe L Rowles, Ronnie Fowle-Grider, Yin Cao, Leah P Shriver, Gary J Patti.

  The deregulated utilization of nutrients by tumors, first observed over a century ago, is recognized as a hallmark of cancer and continues to be exploited clinically to image neoplastic disease. Despite this historic focus on cancer cells and, more recently, their neighbors, metabolic reprogramming is not limited to the tumor microenvironment. Tumors also have the capacity to rewire the metabolism of cells throughout the body, including those at distant sites, often referred to as the tumor macroenvironment. Alterations in the metabolism of noncancerous tissues outside the local tumor ecosystem are gaining attention, but their origins and consequences remain incompletely defined. A deeper understanding of these changes may reveal previously unrecognized signatures of disease and unexplored opportunities for therapeutic intervention.

Keywords:  cachexia; glucose; glutamine; lipids; tumor macroenvironment; whole-body metabolism

DOI:  https://doi.org/10.1016/j.trecan.2026.09.007
Bioresour Bioprocess. 2026 Oct 23. pii: 156. [Epub ahead of print]13(1):

Base editing-mediated exon-specific knockout of glutamine synthetase generates a high-productivity CHO cell line for antibody manufacturing.

Tianting Pu, Chengcheng Wang, Hui Lou, Ye Mi, Saiyi Zhang, Siyu Liu, Zhihua Xiao, Qiyao Wang, Qin Liu, Yajing Liu.

  The Chinese hamster ovary (CHO) cell platform dominates recombinant protein production, with the glutamine synthetase (GS) system widely used for clonal selection. However, we observed variable performance between two commercial CHO lines (ATCC CHO-K1 and CHOZN®), which carry distinct intragenic GS deletions and differential residual transcript levels, raising the possibility that the premature termination codon (PTC) position contributes to this phenotypic divergence. To systematically assess the impact of the PTC position, we used base editing to introduce PTCs into each of the six coding exons of Glul. Among the resulting clonal lines, the exon 7-edited (E7) variant exhibited complete GS ablation and sustained high viability. In fed-batch production of an anti-PD-1 monoclonal antibody, E7 achieved higher titers and specific productivities than CHOZN®, with sustained viability. Our findings demonstrate that PTC location is a key determinant of GS knockout completeness and cellular phenotype, identifying exon 7 as a critical knockout target that offers a defined, exon-resolved strategy for accelerating CHO cell line development and improving recombinant protein titers.

Keywords:  Base editing; Chinese hamster ovary (CHO) cell; Glutamine synthetase; Premature termination codon

DOI:  https://doi.org/10.1186/s40643-026-01150-0
Int J Pharm. 2026 Oct 17. pii: S0378-5173(26)01011-2. [Epub ahead of print]706 127562

From metabolic starvation to precision therapy: engineering amino acid-targeted tumor therapeutics.

Mingyue Wang, Haitao Ding, Lei Xu, Yunkun Li.

  Amino acid metabolism has emerged as a critical nexus linking tumor cell nutrient acquisition with immune microenvironmental regulation, providing a rich source of druggable targets for cancer therapy. Tumor cells engage in fierce metabolic competition with immune cells for key amino acids, including glutamine, arginine, tryptophan, and methionine, thereby establishing an immunosuppressive tumor microenvironment. Over the past decade, therapeutic strategies targeting this metabolic axis have evolved from preclinical proof-of-concept to active clinical development across multiple biotechnology modalities. This review provides a comprehensive overview of amino acid metabolism-targeted therapeutics, emphasizing drug development trajectories and clinical translation prospects. Enzymatic depletion strategies, tumor-selective prodrugs and the clinical development landscape of small-molecule metabolic modulators are analyzed for tumor precision therapy. Despite promising efficacy, clinical translation faces challenges including compensatory metabolic resistance, patient stratification, and the immunosuppressive dichotomy of systemic amino acid depletion. The rational integration of metabolic modulation with immune checkpoint inhibition, chemotherapy, and precision delivery systems holds promise for advancing these therapies into standard oncological practice.

Keywords:  Amino acid metabolism; Drug engineering; Metabolic vulnerability; Tumor therapeutics; Tumor–immune metabolic competition

DOI:  https://doi.org/10.1016/j.ijpharm.2026.127562
Environ Health (Wash). 2026 Oct 16. 4(10): 2199-2207

Global Analysis of Metabolic Fluxes of Glucose and Glutamine in INS‑1 Cells Exposed to Arsenite Using 13C‑Isotopic Tracers.

Ruijia Zhang, Liangyu Chen, Yingshi Lin, Wenhua Lu, Yizheng Li, Yangyang An, Qihong Yan, Xubin Yang, Tiangang Luan, Baowei Chen.

  Human exposure to arsenic has been reported to induce metabolic disorders in pancreatic β-cells. However, metabolic fluxes of essential carbon sources in pancreatic β-cells under arsenic exposure were not quantitatively characterized. In this study, 13C-labeled glucose and glutamine were used as the tracers to examine their fates in INS-1 832/13 cells treated with arsenite (iAsIII). INS-1 832/13 cells exposed to three concentrations of iAsIII (0.05, 0.5, and 1.0 μg/mL) maintained at least 80.0% of cell viability in comparison to the controls. Glucose uptake of INS-1 832/13 cells exposed to 1.0 μg/mL iAsIII was approximately 2 times higher than that of the controls. Accordingly, glucose was also accumulated in the iAsIII-treated INS-1 832/13 cells. The activities of glucose-derived pathways in INS-1 832/13 cells, including glycolysis, tricarboxylic acid (TCA) cycle, and pentose phosphate pathway (PPP), were consistently enhanced by iAsIII. However, mitochondrial respiratory indexes of INS-1 832/13 cells, including oxygen consumption rate (OCR), ATP-linked OCR, basal OCR, maximal respiration, and spare respiratory capacity, were considerably suppressed by iAsIII. Inhibitive effects of iAsIII on metabolic pathway activities of glutamine were observed. Collectively, our results suggest that iAsIII exposure can induce metabolic reprogramming involved with glucose and glutamine in INS-1 832/13 cells.

Keywords:  arsenic exposure; glucose metabolism; metabolic reprogramming; mitochondria; pancreatic β-cells

DOI:  https://doi.org/10.1021/envhealth.5c00614
Anal Chem. 2026 Sep 22. 98(37): 27485-27494

Silver Ion-Regulated Luminescence of Chiral Au-Cysteine Nanoflowers for Highly Effective Enantioselective Recognition of Glutamine.

Li Rong Liang, Ai Tang, Sai Ping Xiang, Ru Hang Song, Yu Qin, Dong Mei Wang, Cheng Zhi Huang, Hong Yan Zou, Shu Jun Zhen.

Rapid and highly effective enantioselective recognition of amino acid enantiomers remains a significant challenge in luminescent sensing. Herein, we develop a silver ion-regulated luminescent sensing platform based on chiral Au-d-Cysteine nanoflowers (Au-d-Cys NFs) for the recognition of glutamine enantiomers. Ag+ coordinates with the amino and carboxyl groups of the ligand, enhancing and modulating ligand-to-metal charge transfer (LMCT) emission of Aud-Cys NFs, while inducing an emission blue shift from 575 to 545 nm. On this basis, the system exhibits distinctly different luminescence responses toward d-Glutamine (d-Gln) and l-Glutamine (l-Gln). d-Gln efficiently quenches the luminescence, whereas l-Gln induces only minimal changes, enabling a high enantioselective discrimination factor of up to 22.25 and allowing quantitative analysis of enantiomeric excess. The recognition process is rapid, reaching completion within 5 min, and permits intuitive visual discrimination under ultraviolet illumination. Mechanistic studies reveal that Ag+-mediated coordination modulation enhances the system's sensitivity to differential enantiomer interactions, which is critical for achieving efficient recognition. This work establishes a coordination-regulated chiral luminescent sensing strategy and provides a new analytical approach for the design of enantioselective sensing systems.

DOI: https://doi.org/10.1021/acs.analchem.6c03808
Biochim Biophys Acta Mol Cell Res. 2026 Oct 22. pii: S0167-4889(26)00138-2. [Epub ahead of print] 120239

Dysregulated PIKfyve-dependent inhibition of ClC-7 causes ammonium-dependent endolysosomal vacuolization and autophagic flux impairment: Rescue by glutaminase inhibition.

Junsuke Uwada, Hitomi Nakazawa, Takashi Yazawa, Ikunobu Muramatsu, Takayoshi Masuoka.

  ClC-7 is a lysosomal 2Cl-/1H+ antiporter essential for normal lysosomal function. PIKfyve-generated PI(3,5)P2 negatively regulates ClC-7 activity, and gain-of-function mutations (e.g., Y715C) that abolish this regulation cause severe genetic disorders. At the cellular level, these variants induce extensive endolysosomal vacuolization accompanied by impaired autophagic flux; however, the precise molecular mechanism driving vacuole enlargement remained elusive. Here, we report that prominent vacuole formation in cells expressing ClC-7 gain-of-function variants is closely associated with a marked intracellular ammonium accumulation. Furthermore, vacuole enlargement was attenuated by an ammonium scavenger and accelerated by exogenous glutamine or ammonium chloride, while pharmacological glutaminase inhibition suppressed both vacuole size and ammonium accumulation. Pharmacological inhibition of PIKfyve likewise induced vacuolization and ammonium accumulation, both of which were suppressed by ClC-7 knockout. Using a newly modified lipid-probe, we found that unlike PIKfyve inhibition, PI(3,5)P2 is maintained on ClC-7 gain-of-function vacuoles. The formation of vacuoles induced by the overexpression of SNX10, which downregulates PI(3,5)P2 synthesis, or by expression of a gain-of-function ClC-6 mutant was also accompanied by a marked accumulation of cellular ammonium. Additionally, cells overexpressing ClC-3 or ClC-5 exhibited vacuolization associated with cellular ammonium accumulation under the control of the accessory protein TMEM9. The impairment of autophagic flux triggered by either ClC-7 gain-of-function expression or PIKfyve inhibition was restored by glutaminase inhibition. Collectively, these findings demonstrate that glutamine-derived ammonium drives endolysosomal vacuolization and autophagic dysfunction downstream of the PIKfyve-ClC-7 axis, identifying glutaminase inhibition as a potential therapeutic strategy for associated genetic disorders.

Keywords:  Ammonia; Autophagy; ClC-7; Endosome; Lysosome; PI(3,5)P(2); PIKfyve

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120239
Front Immunol. 2026 ;17 1928701

Advancing osteosarcoma treatment: the impact of intratumoral metabolic reprogramming on immunotherapy.

Jiawei Yin, Shuai Lu, Yikai Liu, Maoqi Gong, Yejun Zha, Xieyuan Jiang.

  Osteosarcoma (OS) remains difficult to cure once it becomes metastatic, recurrent, or resistant to chemotherapy, and immune checkpoint blockade has provided limited clinical benefit. The metabolic-immune tumor microenvironment (TME) is one barrier to effective immunity because malignant, stromal, and immune cells compete for nutrients and adapt to hypoxia, acidosis, and matrix-related constraints. This review examines how cancer-associated fibroblasts, extracellular matrix, myeloid and lymphoid populations interact with glucose/lactate, glutamine, arginine, and lipid metabolism in OS. Public OS single-cell RNA sequencing datasets are used to illustrate cellular heterogeneity and are interpreted alongside published experimental evidence. OS-specific evidence is most developed for glycolysis and acidosis, glutamine dependence, myeloid regulation, and selected stromal and lipid-related pathways. Arginine-directed approaches, NK-cell immunometabolism, and most metabolism-ICB combinations remain preclinical or are supported mainly by mechanistic evidence from other tumor types. Together, these findings highlight the mechanisms with the strongest current support and the major gaps that remain before clinical translation.

Keywords:  immune checkpoint blockade; immunometabolism; metabolic reprogramming; osteosarcoma; single-cell RNA sequencing; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1928701
Chin Med J (Engl). 2026 Oct 19.

Metabolic processes and microenvironmental regulation in leukemia.

Binhe Chang, Yong Wang, Zijuan Li, Muying Zhao, Chuhan Deng, Yiyi Ren, Qijing Li, Xiaojian Sun, Lan Wang.

   ABSTRACT: Leukemia, a heterogeneous group of hematologic malignancies, continues to present significant therapeutic challenges owing to persistent issues, such as relapse, drug resistance, and treatment-related toxicity. While traditional research has primarily focused on genetic drivers, there is increasing recognition of the critical roles played by the bone marrow microenvironment (BMME) and metabolic reprogramming in disease pathogenesis. This review systematically elucidates the dynamic interplay between these 2 hallmarks of leukemia. We detailed how leukemia cells rewire their metabolic networks to sustain uncontrolled proliferation, emphasizing aberrant activation of glucose metabolism and dynamic remodeling of lipid metabolism via de novo synthesis, uptake, and oxidation. Additionally, we highlighted a critical dependency on specific amino acids, such as glutamine and serine. We investigated the use of BMME to create a protective niche for leukemia cells. These include supportive functions provided by bone marrow stromal cells via direct contact and paracrine signaling, the establishment of an immunosuppressive environment characterized by T cell and natural killer cell exhaustion, an increase in regulatory populations, and the driving force of chronic inflammatory signaling. Importantly, these processes are interdependent, and a reciprocal relationship exists wherein metabolic byproducts from leukemia cells remodel the BMME while simultaneously enabling this microenvironment to dictate metabolic phenotypes in leukemia cells. Targeting the intricate axis between metabolism and the microenvironment is a promising frontier for the development of novel and effective combination therapies against leukemia.

Keywords:  Bone marrow microenvironment; Drug resistance; Immunosuppression; Leukemia cells; Metabolic reprogramming; Stromal niche

DOI:  https://doi.org/10.1097/CM9.0000000000004226
Histopathology. 2026 Oct 20.

Hybrid lesions of hepatocellular adenoma and focal nodular hyperplasia: a clinicopathological and molecular study of two cases.

Yoh Zen, Peter Schirmacher.

   AIMS: Hybrid lesions containing distinct components of hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) within a single nodule are exceptionally rare. This study aimed to investigate the biological nature of these unusual lesions.
METHODS AND RESULTS: The two cases identified to date were examined by histopathological, immunohistochemical and targeted next-generation sequencing analyses. In case 1, the hybrid tumour (6.0 cm) consisted of approximately equal proportions of HNF1α-inactivated HCA and FNH, which were intimately admixed but remained histologically distinct. In case 2, the tumour (9.5 cm) consisted predominantly of HNF1α-inactivated HCA but contained a small peripheral nodule of FNH, resulting in a nodule-in-nodule appearance. The HCA components in both cases showed loss of FABP1 expression, whereas the FNH components retained FABP1 expression and showed a map-like pattern of glutamine synthetase expression. Next-generation sequencing in case 1 demonstrated that the mutations were not shared between the HCA and FNH components, with HNF1A and FLT1 mutations identified only in the HCA component. In case 2, the same HNF1A splice-site mutation was identified in both the HCA and FNH components, but was also present in the non-neoplastic gallbladder, confirming its germline origin. The HCA component, but not the FNH component, additionally harboured somatic mutations in ATM and FAT4.
CONCLUSION: HCA, particularly the HNF1α-inactivated subtype, rarely coexists with FNH. The distinct molecular and immunohistochemical profiles of the two components support a collision mechanism, indicating that the FNH component represents a separate non-neoplastic lesion and arguing against one component arising from the other.

Keywords:  FNH; HCA; HNF1a; collision; glutamine synthetase; hepatocellular adenoma

DOI:  https://doi.org/10.1111/his.70305
ACS Nano. 2026 Oct 06. 20(39): 26728-26755

Prepregnancy Exposure to High Doses of Nanoplastics Triggers Persistent Vaginal Microbiome Dysbiosis to Induce Adverse Pregnant Outcomes.

Wan Liu, Junchang Wang, Wenxin Huang, Xiumei Xiong, Pengming Sun, Yanbing Lin, Yanxin Wang, Depeng Zhao, Wenli Cheng, Qiong Lei, Zhan Qiao, Qingzhen Xie, Shuaishuai Xing, Fang Xiao, Wei Li, Huidong Zhang.

  The global accumulation of nanoplastics poses wide concerns for human health. Although their toxicity in various organs is being uncovered, their impact on vaginal microbiomes that are essential for healthy reproduction remains largely unknown. Here, we discover a previously unrecognized long-term nanoplastic reproductive toxicity that prepregnant exposure to high doses of aged polystyrene nanoparticles (aPS-NPs) induces mouse miscarriage and restricts embryo development by persistently causing vaginal microbial dysbiosis (an increase in Aerococcus urinae abundance), vaginal glutamine depletion (suppression of Slc1a5-mediated import of glutamine from outside cells to intracells), and vaginal inflammation (up-regulation of Ifnar1, Il-1β, and Il-18) from prepregnancy to pregnancy, despite the fact that aPS-NPs are almost undetectable in the vagina on D14 in pregnancy. Transplant of A. urinae into the vaginal tract exacerbates these processes and adverse pregnancy outcomes. Interventions, such as Slc1a5 overexpression, glutamine supplement, or anti-inflammatory treatment, can effectively recover these processes and alleviate the adverse outcomes. Therefore, this study not only demonstrates a previously unrecognized long-term nanoplastic reproductive toxicity by persistently causing vaginal dysbiosis, metabolic dysfunctions, and inflammation, ultimately inducing adverse pregnant outcomes, but also provides experimental basis for targeted therapies to combat the escalating threat of nanoplastic pollution.

Keywords:  Slc1a5-mediated glutamine import; adverse pregnant outcomes; aged polystyrene nanoparticles (aPS-NPs); vaginal glutamine depletion; vaginal inflammation; vaginal microbial dysbiosis

DOI:  https://doi.org/10.1021/acsnano.6c12162
Eur J Pharmacol. 2026 Oct 23. pii: S0014-2999(26)00956-8. [Epub ahead of print] 179474

Gentiopicroside protects against kainic acid-induced excitotoxicity by preserving glutamate homeostasis in rats.

Cheng-Wei Lu, Tzu-Yu Lin, Kuan-Ming Chiu, Ming-Yi Lee, Su-Jane Wang.

  This study provides the first evidence that gentiopicroside, a bioactive constituent isolated from Gentiana scabra, protects against kainic acid (KA)-induced excitotoxicity in rats. Intraperitoneal pretreatment with gentiopicroside (50 mg/kg) 30 min prior to KA administration (15 mg/kg) significantly mitigated seizure severity and prevented KA-induced cerebral blood flow (CBF) deficits. Histological analyses revealed that gentiopicroside markedly attenuated KA-induced neuronal loss, ultrastructural damage, and glial activation in the hippocampus. Mechanistically, gentiopicroside preserved the homeostasis of the glutamate-glutamine cycle, thereby reducing pathologically elevated hippocampal glutamate concentrations. This protective effect was mediated by the upregulation of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS), alongside with the downregulation of glutamine transporters (SNAT1/3), glutaminase, and vesicular glutamate transporter 1 (VGLUT1). Furthermore, gentiopicroside normalized KA-induced alterations in AMPA and NMDA receptor subunit compositions, specifically restoring decreased GluA1, GluA2, and GluN2A levels while suppressing GluN2B upregulation. Additionally, gentiopicroside alleviated KA-induced mitochondrial dysfunction by suppressing calpain expression, restoring calpastatin and mitofusin 2 (MFN2) levels, and downregulating apoptotic protease activating factor 1 (Apaf-1). These findings suggest that gentiopicroside exhibits neuroprotective effects against KA-induced acute glutamate excitotoxicity by maintaining glutamate homeostasis, preventing calpain-mediated mitochondrial impairment, and attenuating glial neuroinflammation. These results highlight its therapeutic potential for excitotoxicity-related neurological disorders.

Keywords:  calpains; excitotoxicity; gentiopicroside; glutamate homeostasis; kainic acid; neuroprotection

DOI:  https://doi.org/10.1016/j.ejphar.2026.179474
Front Nutr. 2026 ;13 1912372

Reduced hepatic GLUL expression accompanies altered RIP3/MLKL-pathway protein abundance in early cholestatic liver injury following bile duct ligation.

Baiyu Yao, Fanhe Xiao, Zhong Tian, Juan Kong.

   Background: Obstructive cholestasis is characterized by disturbances in bile acid homeostasis, amino acid metabolism, inflammatory responses, and hepatocellular injury. Although RIP3/MLKL-pathway proteins have been implicated in cholestatic liver damage, their relationship with metabolic alterations remains incompletely understood. This study aimed to identify necroptosis-related genes and associated metabolic-pathway alterations in early bile duct ligation (BDL)-induced cholestatic liver injury through integrated bioinformatics analyses and experimental validation.
Methods: Gene expression datasets GSE29776 and GSE166867 were retrieved from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and necroptosis-related differentially expressed genes (NRDEGs) were identified. Functional enrichment analyses, protein-protein interaction network construction, least absolute shrinkage and selection operator (LASSO) regression, and random forest analysis were performed to prioritize candidate genes. A murine BDL model was established for validation using biochemical assays, histological analyses, RT-qPCR, and western blotting. Phosphorylated RIP3 and MLKL were evaluated both relative to GAPDH and as phosphorylation-to-total-protein ratios.
Results: Eight NRDEGs were identified, including Tnfaip3, Sqstm1, Chmp2b, Ifngr2, Slc25a4, Ifngr1, Camk2d, and Glul. Functional enrichment analyses revealed significant enrichment in pathways related to metabolic regulation, transmembrane transporter activity, inflammatory signaling, and necroptosis. Machine-learning analyses prioritized Sqstm1, Ifngr1, and Glul as candidates for exploratory characterization. Glul, which encodes glutamine synthetase (GLUL), was markedly downregulated in cholestatic liver tissues. Experimental validation confirmed bile acid accumulation, reduced Glul mRNA expression and GLUL protein abundance, and increased GAPDH-normalized RIP3, p-RIP3, MLKL, and p-MLKL abundance in BDL mice. Both the p-RIP3/RIP3 and p-MLKL/MLKL ratios were significantly increased, supporting enhanced phosphorylation of RIP3 and MLKL relative to the corresponding total-protein levels.
Conclusion: In early BDL-induced cholestatic liver injury, reduced hepatic Glul mRNA expression and GLUL protein abundance occurred concurrently with increased RIP3 and MLKL phosphorylation relative to the corresponding total-protein levels. These findings support enhanced RIP3/MLKL-associated signaling but do not independently establish pathway-dependent necroptotic flux. Further mechanistic validation is required.

Keywords:  GLUL; RIP3/MLKL-related signaling; bile duct ligation; cholestatic liver injury; necroptosis-related genes

DOI:  https://doi.org/10.3389/fnut.2026.1912372
Front Endocrinol (Lausanne). 2026 ;17 1952560

Glucocorticoids in breast cancer: physiologic mechanisms and relationship to risk, survival, and treatment response.

Robert T Chatterton, Peter H Gann.

  Almost every cell of the body expresses glucocorticoid receptors (GR). Cell density, isoform distribution, and responsiveness vary greatly among tissues with highest density in cells of the immune system. Well-documented basic studies describe functions of GR-cortisol complex in immune cells; inhibition of inflammation, promotion of apoptosis, inhibition of proliferation, and inhibition of transport into tissues. Basic studies also describe metabolic actions; promotion of gluconeogenesis, amino acid mobilization, impairment of insulin secretion, inhibition of glucose uptake, and expansion of visceral fat depots. Cortisol secretion is stimulated by psychological stress, and by physiological responses to pain, infection, and hypoglycemia. Stimulatory inputs from the brain on CRH and AVP biosynthesis, deficiencies in the negative feedback of cortisol, and insufficient stimulation of β-arrestin-1 by cortisol may all act to increase secretion of ACTH. Peripherally, cortisol activity is preserved by 11βHSD type I and is decreased at specific sites by 11βHSD type 2. In metastatic breast cancer, the normal circadian rhythm of serum and salivary cortisol is often disrupted, with great hour-to-hour variation and elevated concentrations during the afternoon nadir. Cortisol may increase cancer risk by making glucose available through glycogenolysis and gluconeogenesis, by inhibiting insulin promotion of glucose uptake, and by inhibiting IGF-I promotion of leukocytopoiesis, increasing the synthesis of glutamine synthetase, inhibiting ICAM-I and VCAM-1 for leukocyte recruitment, and increasing the expression of immune checkpoint receptors PD-1 and Tim3, and increasing Treg cells. Cortisol promotes the polarization of macrophages toward the anti-inflammatory M2 phenotype and decreases the M1 phenotype. It also binds to membrane-bound corticosteroid-binding globulin, activating adenylyl cyclase, suppressing T cell proliferation. Overall, elevated cortisol secretion may promote growth of breast cancer by providing a substrate for growth and by suppression of host defenses. However, by antagonizing the estrogen response the liganded receptor may inhibit the growth of estrogen-dependent breast cancer. This review is relevant at this time because of the many interactions of glucocorticoids with potential treatments for the several subtypes of breast cancer. Glucocorticoid agonists may benefit therapies utilizing DNA damage response, retinoid therapy, and PARP1 therapy but may oppose therapies of ER-negative cancers and immune checkpoint blockade therapy.

Keywords:  breast cancer; glucocorticoids; immune system; metabolism; receptors

DOI:  https://doi.org/10.3389/fendo.2026.1952560
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2026 Oct 15. 40(10): 1623-1634

[L-lactylation regulatory network in orthopedic degenerative diseases].

Jianlin Shen, Yiting Xu, Jialin Yang, Miao Xu, Xuan Lin, Xiaoning Lin, Yue Lai, Yunfeng Rui, Huan Liu.

   Objective: To explore the therapeutic potential of L-lactylation in degenerative disc disease, arthritis, muscle degeneration, exercise metabolism, and osteoporosis.
Methods: Literatures about L-lactylation in metabolic regulation, inflammatory response, and bone homeostasis at home and abroad in recent years were extensively reviewed. Emphasis was placed on analyzing the molecular regulatory networks of L-lactylation and its related clinical therapeutic potential in intervertebral disc degenerative diseases, arthritis, muscle degeneration and exercise metabolism, and osteoporosis.
Results: L-lactylation reprograms metabolic flux by modifying key enzymes, and regulates chromatin dynamics through histone/non-histone modifications, thereby modulating macrophage polarization, osteoclast-osteoblast balance, and extracellular matrix remodeling. In intervertebral disc degeneration, tumor necrosis factor α activates glycolytic enzymes to promote L-lactylation, while glutamine supplementation reduces L-lactylation levels and activates the adenosine monophosphate-activated protein kinase catalytic subunit α pathway; hypoxia inducible factor 1α promotes the extracellular transport of L-lactylation by upregulating monocarboxylate transporter 4. In osteoarthritis, lactate dehydrogenase A (LDHA) overexpression leads to elevated histone L-lactylation levels, which in turn upregulates the transcriptional activity of triosephosphate isomerase 1 and accelerates cartilage degradation. In rheumatoid arthritis, artemisinin induces L-lactylation of pyruvate kinase M2 and inhibits the proliferation and migration of fibroblast-like synoviocytes. In tendinopathy, L-lactylation exerts regulatory effects in the aspects of extracellular matrix, immunity, nerves and blood vessels. In osteoporosis, L-lactylation affects osteogenic differentiation and bone resorption through regulatory axes such as Forkhead box F1, crystallin alpha B/ferritin heavy chain 1, and JunB, and interventions including LDHA regulation and scopolamine administration can promote osteogenic differentiation.
Conclusion: L-lactylation plays a dual regulatory role in orthopedic degenerative diseases, and its spatiotemporal dynamics and tissue specificity provide new opportunities for precise treatment. Although target specificity and clinical validation still face challenges, targeting L-lactylation modification is expected to become a new direction for disease-modifying therapy of orthopedic degenerative diseases.

Keywords:  L-lactylation; bone homeostasis; inflammatory responses; metabolic processes; orthopedic degenerative diseases

DOI:  https://doi.org/10.7507/1002-1892.202601143
Oncol Lett. 2026 Nov;32(5): 535

hnRNPC promotes oral squamous cell carcinoma progression via N6-methyladenosine-dependent stabilization of BCAT1 to enhance branched-chain amino acid metabolism.

Zhixin Zhang, Xin Gao, Ting Han, Fei Chai, Menghui Gao, Yulin An.

  Oral squamous cell carcinoma (OSCC) remains a major cause of cancer-associated mortality worldwide, with current treatments limited by chemoresistance and long-term toxicities. N6-methyladenosine (m6A) modification regulates mRNA fate to drive cancer progression. However, how m6A modification regulates OSCC progression remains to be elucidated. The present study integrated bioinformatics analysis of The Cancer Genome Atlas and Genotype-Tissue Expression datasets and experimental validation to explore the role of heterogeneous nuclear ribonucleoprotein C (hnRNPC), an m6A-associated RNA-binding protein, in OSCC. Bioinformatics analysis of 515 patients with head and neck squamous cell carcinoma (HNSCC) suggested that hnRNPC may have prognostic relevance in HNSCC. High hnRNPC expression associated with advanced pathological stages, poor overall survival and served as a potential risk factor for HNSCC. Functional experiments demonstrated that hnRNPC knockdown in OSCC cell lines inhibited cell proliferation, colony formation, tumor sphere formation and in vivo tumor growth, while downregulating stemness-associated genes (Oct4, Sox2 and Nanog). Mechanistically, hnRNPC promoted branched-chain amino acid (BCAA) metabolism in OSCC. High hnRNPC expression was associated with activated BCAA metabolic pathways and hnRNPC knockdown reduced BCAA uptake, glutamate levels, oxygen consumption rate and glutathione levels. Furthermore, hnRNPC stabilized BCCAA transaminase 1 (BCAT1) mRNA in an m6A-dependent manner. BCAT1 inhibition via ERG240 enhanced the tumor-suppressive effects of hnRNPC knockdown. Exogenous supplementation of α-ketoglutarate rescued energy deficiency and functional defects in hnRNPC-knockdown OSCC cells. Collectively, the present study findings revealed a novel mechanism driving OSCC progression. In this mechanism, hnRNPC regulates BCAA metabolism by stabilizing BCAT1 mRNA in an m6A-dependent manner. The present study supports the prognostic relevance of hnRNPC and may offer a promising therapeutic direction in improving OSCC treatment outcomes by disrupting tumor-specific metabolic and epigenetic adaptations.

Keywords:  N6-methyladenosine modification; branched-chain amino acid transaminase 1; heterogeneous nuclear ribonucleoprotein C; oral squamous cell carcinoma

DOI:  https://doi.org/10.3892/ol.2026.15890
Biochim Biophys Acta Mol Cell Res. 2026 Oct 20. pii: S0167-4889(26)00137-0. [Epub ahead of print]1874(1): 120238

Hyperosmotic stress in renal tubular epithelial cells promotes TFEB-dependent autophagy in interstitial fibroblasts by involving extracellular glutamate.

Takashi Miyano, Yoshikazu Yamagishi, Naoya Sakamoto, Toshihiro Sera.

  Renal tubular epithelial-interstitial fibroblast communication maintains kidney homeostasis but promotes disease when dysregulated. Tubular epithelial cells undergo large physiological osmotic fluctuations; however, it remains unclear whether epithelial hyperosmotic stress sends signals to neighboring fibroblasts. Herein, we examined how epithelial hyperosmotic stress regulates fibroblast autophagy and transcription factor EB (TFEB) activity. We used a Transwell co-culture system with rat proximal tubular epithelial cells (NRK-52E) and renal interstitial fibroblasts (NRK-49F), which allowed evaluation of the paracrine effect on fibroblasts mediated by tubular epithelial cells. Hyperosmotic stress in epithelial cells induced the robust nuclear translocation of TFEB in fibroblasts, increased the expression of lysosomal and autophagy-related genes, and enhanced autophagic flux without altering fibroblast viability or proliferation. Although fibroblasts internalized epithelial-derived extracellular vesicles, they did not activate TFEB, suggesting an extracellular vesicles-independent mechanism. RNA sequencing revealed that hyperosmotic stress markedly alters the expression of epithelial solute carrier genes, particularly those encoding amino acid transporters. Analysis of amino acid metabolism revealed corresponding changes in conditioned media, including an increase in extracellular glutamate. Glutamate alone induced TFEB nuclear translocation and autophagy activation in fibroblasts. Both epithelial hyperosmotic co-culture and glutamate treatment activated AMP-activated protein kinase and inhibited mTORC1 signaling, thereby enabling TFEB activation. These results identify extracellular glutamate as a metabolite-based paracrine signal that couples epithelial osmotic stress with TFEB-dependent autophagy in interstitial fibroblasts.

Keywords:  Autophagy; Hyperosmotic stress; Interstitial fibroblasts; Renal tubular epithelial cells; TFEB

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120238
Free Radic Biol Med. 2026 Oct 20. pii: S0891-5849(26)01227-X. [Epub ahead of print]257 630-648

Deubiquitination of WBP11 governs OPLAH-mediated glutathione biosynthesis to suppress triple programmed cell death in prostate cancer.

Xuefen Zhuang, Wanying He, Jiangyu Zhang, Zixuan Wang, Kaixing Zheng, Yanqi Zhuang, Zilong Song, Wenshuang Sun, Zhenlong Shao, Xiaodong Fu, Yuning Liao.

  Prostate cancer (PC) is one of the most common male cancers. Cancer cells are well known for their capacity to avoid programed cell death (PCD) via a variety of molecular pathways, allowing them to survive oncogenic stress and therapeutic challenges. Although oncogenic splicing factors are frequently dysregulated in tumors, their functional interplay with PCD regulatory networks in PC remains largely uncharacterized. Here, we demonstrate that WBP11 exerts a pro-tumorigenic effect by promoting PC cell proliferation, while its genetic silencing triggers concurrent induction of apoptosis, pyroptosis, and ferroptosis. Mechanistically, WBP11 directly binds to and stabilizes OPLAH mRNA, leading to elevated intracellular glutathione levels that facilitate efficient clearance of reactive oxygen species (ROS). Additionally, we demonstrate that USP13 deubiquitinates WBP11 by specifically eliminating K48-linked ubiquitin chains at lysine 626, which increases the stability of the WBP11 protein and prevents proteasomal destruction. Using a combination of in vitro functional assays, in vivo tumor models, and systematic rescue experiments, we define a previously unrecognized signaling axis, USP13-WBP11-OPLAH, that orchestrates glutathione metabolism and confers resistance to PCD, ultimately driving malignant progression of PC. Consistent with these functional findings, clinical validation reveals that USP13, WBP11, and OPLAH are significantly upregulated at the protein level in human PC tissues, and that USP13 expression positively correlates with both WBP11 and OPLAH protein abundance. Collectively, our study identifies the USP13-WBP11-OPLAH axis as a critical regulatory module linking glutathione metabolism to PCD resistance, offering promising therapeutic targets for the treatment of advanced PC.

Keywords:  Glutathione; OPLAH; Prostate cancer; USP13; WBP11

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.036
Mol Biomed. 2026 Oct 23. pii: 223. [Epub ahead of print]7(1):

Citrullinated histone H3 and elevated polyamine metabolism gene expression in peripheral blood polymorphonuclear leukocytes as biomarkers for poor immunotherapy response in cancer patients.

Amy Anzovino, Stephanie Kjelstrom, Kathryn Fleck, Margaretha Wallon, Eric T Alexander, Susan K Gilmour.

  There is a critical need to identify validated biomarkers that can predict cancer patient outcomes. This study evaluated biomarkers of neutrophil extracellular traps (NETs) and polyamine gene expression in peripheral blood that may correlate with greater risk for poor response to immunotherapy. Peripheral blood collected from cancer patients being treated with chemo/immunotherapy and from healthy volunteers was analyzed for levels of citrullinated histone H3 (Cit H3, a NETosis marker), inflammatory cytokines, and circulating tissue factor positive microparticles (TF+MPs). Elevated levels of plasma TF+MPs, Cit H3, IL-8, and IL-6 each significantly correlated with poor response to immunotherapy. Since in vitro stimulation of both human and mouse neutrophils to form NETs was blocked with addition of an inhibitor of polyamine uptake (Trimer44NMe), RNA expression of polyamine/glutamine metabolism genes was evaluated in both peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes (PMN). Elevated expression of glutamine-associated genes in PBMCs and decreased expression of polyamine-associated genes in PMN correlated with favorable patient response to immunotherapy. Although not reaching significant levels, a high overall polyamine score in peripheral PMNs as well as increased plasma Cit H3 levels correlated well with poor response to immunotherapies in cancer patients. In a mouse model of triple negative breast cancer, polyamine blocking therapy inhibited not only primary tumor growth and lung metastases but also decreased intratumor NETs. Results from this study suggest a mechanistic link between NETosis and polyamine gene expression in PMN that warrant further investigation as peripheral blood biomarkers for immunotherapy response.

Keywords:  Blood biomarkers; Cancer immunotherapy; Glutamine; Neutrophil extracellular traps; Polyamines

DOI:  https://doi.org/10.1186/s43556-026-00644-9
PLoS One. 2026 ;21(10): e0352911

Structure bioinformatics of eight human ATP synthase F0 subunits and their AlphaFold3-predicted reduced-hydrophobicity QTY analogues.

Ziyu Wang, Edward Chen, Shuguang Zhang.

Human mitochondrial ATP synthase is an essential rotary motor enzyme that produces most of the cellular ATP through oxidative phosphorylation. Its membrane-embedded F0 sector contains highly hydrophobic transmembrane subunits that are challenging to study in aqueous environments without detergents. We applied the QTY code to eight human ATP synthase F0 subunits: ATP6, ATP8, ATPK, ATP68, ATPMK, AT5G1, AT5G2, and AT5G3. Hydrophobic amino acids leucine (L), isoleucine (I), valine (V), and phenylalanine (F) in transmembrane regions were systematically replaced with hydrophilic glutamine (Q), threonine (T), and tyrosine (Y). Four native subunits with available CryoEM structures from human ATP synthase (PDB: 8H9S) were superposed with their AlphaFold3-predicted QTY analogues. For subunits without complete CryoEM structures, AlphaFold3-predicted native structures were superposed with their AlphaFold3-predicted QTY analogues. Additional structural analyses were included, and key structural and functional regions, including ATP68 and the ATP6-c-ring interface, were modeled. The native ATP synthase F0 subunits superposed well with their respective QTY analogues. For the CryoEM-native comparisons, RMSD values ranged from 0.565 Å to 6.952 Å. For the AlphaFold3-native comparisons of subunits without CryoEM structures, RMSD values ranged from 0.204Å to 0.297Å. Considering all eight subunits, despite substantial QTY substitutions in the transmembrane regions, ranging from 38.89% to 50.79%, the QTY analogues retained similar overall folds, molecular weights, and isoelectric points. Hydrophobic surface analysis showed that the QTY analogues had reduced hydrophobic surfaces compared with their native counterparts. These structural bioinformatics studies suggest that the QTY code is applicable to ATP synthase F0 subunits to generate more hydrophilic, water-soluble analogues while preserving overall structural similarity. These results extend the application of the QTY code to the membrane-embedded F0 sector of ATP synthase and provide a foundation for future experimental studies for these QTY analogues expressed, purified, and evaluated for self-assembly.

DOI: https://doi.org/10.1371/journal.pone.0352911