bims-glucam 2026-07-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–07–26
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

ANLN: A New Hub in Glutamine Metabolism of Lung Adenocarcinoma by scRNA-Seq and Machine Learning.
SFRP2+ CAFs Expressing Myofibroblastic Phenotype Are Involved in Glutamine Metabolism and Malignant Behaviors of Laryngeal Squamous Cell Carcinoma by Collaborating With ELAVL1 to Stabilize GID8 mRNA.
LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.
Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.
Amino Acid Metabolic Enzymes in Gastric Cancer: Roles and Mechanisms in Tumorigenesis and Progression.
Proteomic and amino acid profiling of SK-MEL-30 melanoma reveals metabolic and structural changes.
Translational resistance to amino acid starvation in breast cancer cells revealed by ribosome profiling.
Comprehensive multi-omics approach to investigate the association between metabolic syndrome and pituitary neuroendocrine tumor risk in UK biobank: A cohort study.
Congenital portosystemic shunt (CPSS)/Abernethy malformation: morpho-molecular aspects of a rare hepatic tumour risk disease.
Glutamine and partially hydrolyzed guar gum promote intestinal adaptation and modulate small intestinal microbiota in high-output stoma: A case report.
Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.
Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.
Cystine Restriction Alleviates T Cell Exhaustion and Enhances CAR-T Cell Potency.
Long noncoding RNA MNX1-AS1 mediated regulation of one-carbon metabolism by preventing CACYBP degradation to promote lung cancer progression.

Oncol Res. 2026 ;34(8): 20

ANLN: A New Hub in Glutamine Metabolism of Lung Adenocarcinoma by scRNA-Seq and Machine Learning.

Yiming Ma, Zhihan Zhang, Hongli Pan, Hailin Jiang, Lili Guo, Fengjie Guo.

   OBJECTIVES: Lung adenocarcinoma (LUAD) has a poor prognosis, and effective metabolic biomarkers are still few. Glutamine metabolism is one of the central features of tumor metabolic reprogramming, but the cellular heterogeneity and clinical significance of glutamine metabolism in the LUAD tumor microenvironment (TME) remain unknown. The goal of this paper was to define glutamine metabolism on a single-cell basis and determine major regulators that have predictive value.
METHODS: A single-cell RNA sequencing dataset (GSE149655) was combined with The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus (GEO) datasets in order to evaluate the metabolic activity and intercellular communication. The prognostic model was constructed on weighted gene co-expression network analysis (WGCNA), machine learning-based approaches, and least absolute shrinkage and selection operator (LASSO)-Cox regression to examine the characteristics of the immune system and sensitivity to drugs. Carried out CRISPR/Cas9 knockout experiments to prove the function of ANLN.
RESULTS: Glutamine metabolism activity and increased cell-cell communication were observed in mast cells. A gene signature of 4 genes (ANLN, CIP2A, MEST, WDR76) divided the patients into high-risk and low-risk groups; the survival of these two groups, immunosuppressant features of TME, and susceptibility to dasatinib were different. ANLN was also determined to be an essential prognostic driver, and downregulating it inhibited glutamine metabolism and the invasion properties of LUAD cells.
CONCLUSIONS: Mast cells are metabolic centers of LUAD, whereas ANLN is a mediator of the association between glutamine metabolism and the development of tumors, which offers possible treatment options to achieve precise prognostication and treatment goals.

Keywords:  ANLN; Lung adenocarcinoma; Prognostic model; Single-cell RNA-seq; mast cells; metabolism of glutamine; tumor microenvironment

DOI:  https://doi.org/10.32604/or.2026.079515
Mol Carcinog. 2026 Jul 19.

SFRP2+ CAFs Expressing Myofibroblastic Phenotype Are Involved in Glutamine Metabolism and Malignant Behaviors of Laryngeal Squamous Cell Carcinoma by Collaborating With ELAVL1 to Stabilize GID8 mRNA.

Bo Pang, Ying Zhang.

  Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the demands of rapid growth and survival. Within tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) influence tumor metabolism through metabolic crosstalk. However, role of CAF-derived factors in regulating glutamine metabolism in laryngeal squamous cell carcinoma (LSCC) remains unclear. Primary fibroblasts were isolated from LSCC tumors and adjacent tissues and classified as CAFs or normal fibroblasts (NFs). These were co‑cultured with LSCC cell lines to assess effects on proliferation, migration, invasion, stemness, and chemoresistance using assays such as CCK‑8, EdU, sphere formation, Transwell migration/invasion, and real‑time RTCA assays. Exosomes were harvested from fibroblast-conditioned media, characterized by TEM, NTA, and Western blotting, and used to treat LSCC cells. Metabolic profiling included Seahorse measurements, TCA metabolites, ATP content, glutamine uptake ([3H]-glutamine assay), glutamine consumption, as well as glucose consumption and lactate production assays. Mechanistic studies involved manipulating gene expression via transfection, and detection of targets by qRT‑PCR, Western blotting, and histological staining. Interaction of SFRP2, ELAVL1, and GID8 was assessed via Co‑IP and RIP assays. SFRP2 was increased in LSCC and linked to advanced stage, lymph node metastasis, and poor survival. It was mainly produced by a unique group of CAFs with myofibroblastic traits. Exosomal SFRP2 from these CAFs promoted glutamine uptake, mitochondrial activity, and aggressive tumor behaviors. Mechanistically, SFRP2 stabilized GID8 mRNA via ELAVL1 and promoted β-catenin nuclear translocation, activating canonical Wnt signaling. A novel CAF-driven SFRP2-ELAVL1-GID8 pathway promotes metabolic reprogramming involving in LSCC progression.

Keywords:  embryonic lethal abnormal vision‐like protein 1 (ELAVL1); glucose‐induced degradation protein 8 homolog (GID8); glutamine metabolism; laryngeal squamous cell carcinoma (LSCC); secreted frizzled‐related protein 2‐positive cancer‐associated fibroblasts (SFRP2+ CAFs)

DOI:  https://doi.org/10.1002/mc.70138
Cell Death Dis. 2026 Jul 20. pii: 649. [Epub ahead of print]17(1):

LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.

Zhefang Wang, Qiu Huang, Jiangang Zhao, Zicheng Lyu, Feng Ju, Bo You, Jie Wang, Qiongzhu Dong, Margarete Odenthal, Alexander Quaas, Kalliope N Diakopoulos, Hana Algül, Maximilian Reichert, Christiane J Bruns, Yue Zhao.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its aggressive biology and therapeutic resistance. Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and linked to poor prognosis, yet its context-dependent roles in metabolic subtypes and chemoresistance remain undefined. Here, we show that LSD1 knockdown has opposing, subtype-specific effects on chemotherapeutic responses: it sensitized RSK-subtype cells (L3.6pl, PANC-1) to chemotherapy but induced resistance in KRAS-subtype cells (BxPC-3, TBO368). Integrated analyses revealed mitochondrial dysfunction and defective mitophagy as hallmarks distinguishing KRAS- from RSK-subtype PDAC. Critically, mitochondrial targeting through respiratory modulation or mitophagy manipulation overrides LSD1-mediated subtype-specific chemoresistance, establishing mitochondrial fitness as the mechanistic determinant. Mechanistically, LSD1 transcriptionally regulates GLS2 to drive glutamine metabolic reprogramming, promoting reductive carboxylation in KRAS-subtype cells and oxidative metabolism in RSK-subtype cells. Our work establishes the LSD1-GLS2 axis as a metabolic switch controlling PDAC chemosensitivity and provides a framework for subtype-specific therapeutic strategies.

DOI: https://doi.org/10.1038/s41419-026-09075-4
Front Immunol. 2026 ;17 1878140

Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.

Jingyun Chen, Xin Wang, Meiheng Gong, Yufeng Wang, Tingting Yu.

  Tumor immune escape is increasingly recognized as an immunometabolic process shaped not only by immune checkpoints and suppressive cell populations, but also by nutrient competition and metabolic signaling within the tumor microenvironment. This nutrient-competitive environment is not limited to tryptophan depletion, but also involves glucose restriction, glutamine dependence, arginine metabolism, amino acid transporter competition, and impaired mitochondrial fitness of effector T cells. Among amino acid pathways, tryptophan metabolism has emerged as a central regulator of tumor-immune interactions. Through the activity of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), kynurenine-producing branches, and both AHR-dependent and AHR-independent downstream programs, tumors establish a metabolic state that couples tryptophan depletion, metabolite signaling, redox adaptation, and immune suppression. Recent evidence further shows that tryptophan metabolism is not restricted to tumor cells, but also involves cancer-associated fibroblasts, macrophages, and T cells, thereby shaping multicellular crosstalk within immunosuppressive niches. Beyond immune suppression, this pathway contributes to ferroptosis resistance, stemness, metastatic adaptation, and resistance to chemotherapy, targeted therapy, and immune checkpoint blockade. In parallel, circulating metabolites and tissue-level metabolic profiling are being explored as potential biomarkers for patient stratification and treatment response prediction. In this review, we summarize the molecular basis of tryptophan catabolism in cancer, discuss its role in tumor-immune-stromal communication, and highlight emerging translational and therapeutic opportunities. Rather than reviewing tryptophan metabolism as a linear IDO1/TDO2-centered pathway, we define it as a multicellular immunometabolic communication network in which tumor cells, stromal fibroblasts, myeloid cells, and lymphocytes exchange metabolic and signaling cues to create spatially organized immunosuppressive niches. This network-based view helps explain why single-enzyme inhibition is often insufficient and supports the development of biomarker-guided, multi-branch, and cell-context-specific therapeutic strategies.

Keywords:  immunometabolism; kynurenine; tryptophan metabolism; tumor immune escape; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1878140
Oncol Res. 2026 ;34(8): 6

Amino Acid Metabolic Enzymes in Gastric Cancer: Roles and Mechanisms in Tumorigenesis and Progression.

Zixin Wan, Jingdan Quan, Yue Qiu, Zhiwei Zhang.

  Gastric cancer (GC) is one of the malignant tumors with high incidence and mortality worldwide. It has concealed early symptoms, poor prognosis for advanced patients, and limited efficacy of conventional treatments. Metabolic reprogramming is a core hallmark of cancer, among which amino acid metabolic reprogramming plays a critical regulatory role in the initiation and progression of GC. By linking intracellular energy supply, biosynthetic demands, and tumor microenvironment remodeling, it participates in immune escape, redox homeostasis maintenance, and therapeutic resistance. Dysregulation of key amino acids, including arginine, tryptophan, glutamine, branched-chain amino acids, serine/glycine, and aspartic acid, as well as altered expression and activity of rate-limiting enzymes and key catalytic enzymes, collectively drive the proliferation, invasion, metastasis, and stemness maintenance of GC cells. These metabolic enzymes can serve as potential biomarkers for the diagnosis and prognosis of GC, and are also important targets for precision therapy. At present, progress has been made in the development of inhibitors targeting key enzymes in amino acid metabolism. Single-target therapy or its combination with chemotherapy and immunotherapy has shown promising application prospects, but challenges such as clinical translation bottlenecks and unclear drug resistance mechanisms still exist. This review systematically summarizes the roles and molecular mechanisms of key amino acid metabolic enzymes in the occurrence and development of GC, and sorts out the research status of related targeted therapies, so as to provide references for basic research and clinical translation of metabolic precision therapy for GC.

Keywords:  Gastric cancer (GC); arginine; branched-chain amino acids; glutamine; metabolic enzyme; tryptophan; tumor microenvironment

DOI:  https://doi.org/10.32604/or.2026.082561
Anal Biochem. 2026 Jul 18. pii: S0003-2697(26)00161-2. [Epub ahead of print]718 116205

Proteomic and amino acid profiling of SK-MEL-30 melanoma reveals metabolic and structural changes.

Nebiye Pelin Turker.

  Melanoma exhibits high metastatic potential and therapy resistance, driven by metabolic flexibility and structural remodeling. In this study, we performed an integrated analysis of the SK-MEL-30 melanoma cell line using function-focused quantitative proteomics and amino acid profiling. Proteins were quantified using a label-free normalized spectral abundance factor (NSAF) approach, while intracellular amino acids were measured by LC-MS/MS. Functional enrichment analyses based on KEGG and Gene Ontology were used to associate protein expression patterns with metabolic pathways. A total of 148 proteins were identified, predominantly representing high-abundance and functionally relevant components of metabolic and structural pathways. Key cytoskeletal proteins, including vimentin and S100A11, were among the most abundant, consistent with a mesenchymal-like and potentially invasive phenotype. Metabolic profiling revealed elevated expression of glycolytic enzymes such as PKM and LDHA, consistent with a glycolytic shift. Increased levels of l-glutamine and l-glutamic acid, together with GOT2 expression, suggest an active glutamine aspartate axis supporting tricarboxylic acid cycle activity and nitrogen metabolism. In addition, elevated levels of stress-response proteins, including HSP90 and SOD2, indicate a proteostatic network adapted to metabolic stress. Although the proteome coverage is lower than that reported in large-scale deep proteomic studies, the NSAF-based workflow was designed to capture the most abundant and functionally relevant proteins, providing a focused overview of the major metabolic and structural characteristics of SK-MEL-30 melanoma cells. Overall, this integrative analysis highlights the coordination between metabolic reprogramming and cytoskeletal organization in SK-MEL-30 cells and suggests that glutamine-dependent metabolic pathways warrant further investigation as potential therapeutic targets in melanoma.

Keywords:  Amino acid metabolism; GOT2; Melanoma; NSAF; Quantitative proteomics; SK-MEL-30; Vimentin; Warburg effect

DOI:  https://doi.org/10.1016/j.ab.2026.116205
iScience. 2026 Jul 17. 29(7): 116627

Translational resistance to amino acid starvation in breast cancer cells revealed by ribosome profiling.

Fajin Li, Siqiong Zhang, Haoran Duan, Dieter A Wolf, Xuerui Yang.

  Translation elongation is highly sensitive to amino acid availability, with deprivation causing ribosome pausing at cognate codons, suppression of the mammalian target of rapamycin (mTORC1) signaling pathway, and GCN2-mediated phosphorylation of eIF2α. However, cell-type heterogeneity in these responses remains unclear. Integrating ribosome profiling datasets across over ten human cell lines and multiple starvation conditions, we uncover translational resistance in breast cancer cells specifically under leucine and glutamine deprivation. Unlike non-breast cancer cells, breast cancer cells maintain ribosome occupancy on mRNAs with a 5' terminal oligopyrimidine tract (5'TOP mRNAs), indicating sustained mTORC1 activity, and exhibit attenuated codon-specific pausing. GCN2-eIF2α pathway activation varies among breast cancer lines. Downregulation of the cystine/glutamate transporter SLC7A11 correlates with this resistance, and its overexpression restores sensitivity by reducing S6K phosphorylation while enhancing eIF2α phosphorylation. Our findings reveal that breast cancer cells adaptively reshape translation regulation to withstand amino acid starvation, highlighting a potential metabolic vulnerability.

Keywords:  amino acid starvation; mTORC1; ribosome profiling; sensitivity; translation elongation

DOI:  https://doi.org/10.1016/j.isci.2026.116627
Endocr Pract. 2026 Jul 23. pii: S1530-891X(26)01080-3. [Epub ahead of print]

Comprehensive multi-omics approach to investigate the association between metabolic syndrome and pituitary neuroendocrine tumor risk in UK biobank: A cohort study.

PengWei Lin, YuZhe Wang, Zhen Ye, NiDan Qiao, ZengYi Ma, AiShun Guo, Zhao Ye.

   OBJECTIVE: Metabolic syndrome (MetS) is a cluster of metabolic disorders linked to cancer development and progression. The pituitary gland plays a central role in systemic metabolic homeostasis. However, the contribution of metabolic disorders to pituitary neuroendocrine tumor (PitNET) pathogenesis remains poorly understood.
METHODS: We analyzed data of 355,139 participants from the UK Biobank with complete MetS data, with no prior PitNET at baseline. Cox proportional hazards models estimated associations between MetS and incident PitNET, whereas bidirectional Mendelian randomization (MR) assessed causality and minimized reverse-causation bias. Machine learning, multi-omics approaches and single-cell transcriptomic analyses were applied to identify consensus genes and determined cell-type enrichment shared between MetS and PitNET.
RESULTS: Over a median follow-up of 13.0 years, 392 PitNET cases occurred among 135,686 participants with MetS. MetS was associated with a higher risk of PitNET (hazard ratio [HR] 1.57; 95% confidence interval [CI] 1.28-1.93) after model adjustment, with findings in sensitivity analyses. Bidirectional MR provides suggestive evidence consistent with a causal effect of MetS on PitNET risk (odds ratio [OR] 1.38; 95%CI 1.04-1.88; P=0.041) and found no evidence of reverse causation (P>0.05). Integrative multi-omics, machine-learning and single-cell analyses, validated in clinical cohorts, revealed pronounced cellular heterogeneity across PitNET subtypes and the tumor microenvironment, with enrichment of metabolic pathways-including cholesterol, lipid, and glutamine metabolism.
CONCLUSION: These findings support an association of MetS and PitNET pathogenesis. The identified metabolic signatures provide insights into disease mechanisms, may facilitate early identification of high-risk individuals, and highlight potential targets for metabolism-oriented prevention and therapy.

Keywords:  Metabolic syndrome; UK Biobank; multi-omics and machine-learning analyses; pituitary neuroendocrine tumor; risk factors

DOI:  https://doi.org/10.1016/j.eprac.2026.07.015
Virchows Arch. 2026 Jul 23.

Congenital portosystemic shunt (CPSS)/Abernethy malformation: morpho-molecular aspects of a rare hepatic tumour risk disease.

Anne Kristin Fischer, Janna Siemanowski-Hrach, Carina Heydt, Kathrin Hauptmann, Reinhard Büttner, Hans-Peter Fischer.

  Liver tissue in congenital portosystemic shunt (CPSS) is analysed for morphologic and molecular genetic alterations with special regard to hepatocarcinogenesis. The material comprises 8 cases of CPSS between 1.5 and 65 years. Beyond lacking portal veins as the characteristic finding of CPSS, liver arteries were part of the malformative vascular disease. Lack of portovenous perfusion, hyperplasia, obliterating intimal fibrosis, absence of arterial branches, arteriovenous shunting and intralobular arterioles caused disarrangement of the liver parenchyma. Atypical expression of glutamine synthetase (GS) mirrored zonal dysfunctionality of the lobular parenchyma. Three cases contained four nodular lesions. Two hepatocellular carcinomas (HCC) were surrounded by peritumoral nodular hyperplasia with dysplastic changes. One HCC and surrounding precursor lesions strongly expressed GS and nuclear β-catenin, but displayed wild-type CTNNB1 sequences, indicating functional β-catenin activation. The other HCC tested positive for nuclear β-catenin staining in few tumour cells and carried two activating β-catenin mutations in exons 3 and 7. Another activating β-catenin mutation in exon 3 was detected in peritumoral nodules and background liver tissue > 1.0 cm away from the HCC in decreasing frequency. An HNF1A-inactivated hepatocellular adenoma coincident with a focal nodular hyperplasia harboured two different mutations in HNF1A. hTERT promotor mutation or events in other genes involved in HCC development, angiogenesis and angioproliferation were found in neither tumour tissue nor the background liver. Pathological vascularisation, followed by altered zonation, appears to be the basis for functional or mutational activation of β-catenin-driven tumour development in CPSS. Our findings underline CPSS as a tumour risk disease.

Keywords:  Ammonia metabolism; Congenital portosystemic shunt; Glutamine synthetase; HCC carcinogenesis; Liver zonation; β-catenin

DOI:  https://doi.org/10.1007/s00428-026-04641-9
JPGN Rep. 2026 Mar 23.

Glutamine and partially hydrolyzed guar gum promote intestinal adaptation and modulate small intestinal microbiota in high-output stoma: A case report.

Yunosuke Kawaguchi, Keita Terui, Ayako Takenouchi, Shugo Komatsu, Ryohei Shibata, Katsuhiro Nishimura, Shota Takiguchi, Yukiko Iwase, Rei Hashimoto, Keisuke Matsusaka, Yoshiteru Osone, Jun-Ichiro Ikeda, Tomoro Hishiki.

  We report a case of a very low-birth-weight infant with a high-output stoma following necrotizing enterocolitis. The patient exhibited villous atrophy and microbial dysbiosis. Supplementation with glutamine and partially hydrolyzed guar gum (PHGG) was initiated, leading to reduced stoma output, improved feeding tolerance, and appropriate weight gain. Histological analysis revealed villous elongation, and microbiota analysis showed a shift from Proteobacteria dominance to increased Firmicutes and Actinobacteria abundance, along with increased alpha diversity. These findings suggest that glutamine and PHGG may support intestinal adaptation and microbiota modulation in infants with high-output stomas. However, conclusions should be drawn cautiously due to the limited generalizability of a single case.

Keywords:  enterocolitis; mucosal; pediatric

DOI:  https://doi.org/10.1002/jpr3.70169
Acta Neuropathol. 2026 Jul 23. pii: 10. [Epub ahead of print]152(1):

Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.

Matthew Pun, Akash Deogharkar, Siva Kumar Natarajan, Nicholas Nuechterlein, Wentao Tian, Sunjong Ji, Eleanor Young, Fusheng Yang, Debra Hawes, Anthony C Andren, John Henry Owen, Sagar Rau, Fengyun Su, Xuhong Cao, Abhijit Parolia, Mark Prince, Joshua Fry, Paul A Gardner, Rendong Yang, Alexander R Judkins, Carl J Koschmann, Andrew S Venteicher, Costas A Lyssiotis, Arul M Chinnaiyan, Sriram Venneti.

  Chordomas are rare cancers that arise along the axial skeleton. Alterations in metabolism are a hallmark of cancer, and we sought to identify metabolic vulnerabilities in chordoma. We discovered that the tricarboxylic acid (TCA)-related enzyme isocitrate dehydrogenase-1 (IDH1) was expressed highly in bulk and single-cell patient-derived chordomas and was associated with worse survival outcomes. IDH1 catalyzes the conversion of isocitrate and nicotinamide adenine dinucleotide phosphate (NADP+) to alpha-ketoglutarate (⍺-KG) and NADPH. This critical reaction influences TCA cycle metabolism, regulates epigenetic pathways, and affects redox balance. Both IDH1 knockdown and treatment with an inhibitor targeting IDH1 were toxic to chordoma cells. An integrated analysis of the transcriptomic, chromatin, and metabolomic responses on IDH1 inhibition converged on deregulated glutathione metabolism. IDH1 inhibition was associated with increased expression and enrichment of activating H3K27ac at NRF2 (nuclear factor erythroid 2-related factor 2) signature genes including those in the glutathione biosynthetic pathway. This was accompanied by reduction of both NADPH/NADP+ and reduced/oxidized glutathione (GSH/GSSG) ratios. Importantly, IDH1 inhibitor-driven toxicity was rescued via media supplementation with the antioxidant N-acetylcysteine, suggesting that IDH1 inhibition in chordomas creates a redox-dependent metabolic vulnerability. Finally, IDH1 inhibitor treatment reduced tumor growth in two independent chordoma mouse xenograft models. Our findings suggest a potential therapeutic avenue for further exploration in chordoma.

Keywords:  Chordoma; IDH1; Metabolism; NRF2; Redox

DOI:  https://doi.org/10.1007/s00401-026-03048-9
Aging Cell. 2026 Aug;25(8): e70639

Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.

Heng Zhang, Guangyu Liang, Anding Liu.

  During aging, hepatic structural, metabolic, and regulatory impairments collectively contribute to the decline of hepatic and systemic function. As a core hepatic physiological process, ammonia metabolism is essential for maintaining systemic nitrogen homeostasis. However, how ammonia metabolism is altered during aging, and whether these changes contribute to hepatic and systemic decline, remain insufficiently understood. In this review, current evidence linking hepatic ammonia metabolism to liver aging is summarized. The major pathways of hepatic ammonia disposal, including the urea cycle and glutamine synthesis, are first outlined. Age-related changes in these pathways are then discussed, with emphasis on mitochondrial dysfunction, altered post-translational regulation, transcriptional and epigenetic remodeling, and disruption of metabolic zonation. Emerging evidence that ammonia functions not only as a nitrogen waste product but also as a bioactive stress signal is also reviewed. In this context, ammonia has been implicated in mitochondrial injury, senescence-associated signaling, proteostasis defects, and inflammatory and fibrogenic remodeling. The systemic consequences of ammonia dysregulation are further considered, particularly along the liver-brain, liver-muscle, and liver-gut axes. Finally, current and emerging therapeutic strategies are evaluated, including ammonia-lowering agents, senotherapeutics, and microbiota-directed approaches. Collectively, this review identify ammonia metabolism as an underappreciated but potentially axis for understanding liver aging, thereby providing a framework for future mechanistic and translational studies.

Keywords:  aging; ammonia; liver

DOI:  https://doi.org/10.1111/acel.70639
Cancer Res. 2026 Jul 21.

Cystine Restriction Alleviates T Cell Exhaustion and Enhances CAR-T Cell Potency.

Xiaoxue Pan, Yuhang Yin, Haopeng Hong, Jichang Li, Jing Zhu, Xin Wang, Yucun Liu, Pengyuan Wang, Shanwen Chen.

While chimeric antigen receptor (CAR) T cell therapy has demonstrated significant efficacy in treating hematological malignancies, its application in solid tumors remains challenging. A major limitation of CAR-T cell efficacy in solid tumors is the functional exhaustion of CD8⁺ T cells. Here, we investigated metabolic regulators of CD8⁺ T cell exhaustion, identifying that cystine promotes CD8+ T cell exhaustion. RNA sequencing analysis of an in vitro exhaustion model revealed that SLC7A11 was significantly upregulated in exhausted CD8⁺ T cells. A monoclonal antibody specifically targeting SLC7A11 was subsequently generated, and its binding affinity was rigorously validated. Single-cell RNA sequencing and functional studies demonstrated that inhibition of SLC7A11 promoted the expansion of CD8⁺ stem-like memory T cells and alleviated T cell exhaustion. In vivo, treatment with the anti-SLC7A11 antibody enhanced the antitumor efficacy of CAR-T cells. Mechanistically, SLC7A11 inhibition suppressed cystine uptake, which activated the GCN2-eIF2α-SLC1A5 signaling axis. Upregulation of SLC1A5 increased glutamine uptake to stimulate oxidative phosphorylation and support mitochondrial fitness. Together, these findings demonstrate that cystine restriction alleviates CD8+ T cell exhaustion and enhances the efficacy of CAR-T cell therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4375
Cell Death Differ. 2026 Jul 23.

Long noncoding RNA MNX1-AS1 mediated regulation of one-carbon metabolism by preventing CACYBP degradation to promote lung cancer progression.

Juze Yang, Xinyi Qian, Jiayi Ren, Tengfei Sun, Yun Ma, Jia Li, Honghe Zhang, Bingjian Lu, Enguo Chen, Yan Lu, Pengyuan Liu.

Lung cancer remains the leading cause of cancer-related death worldwide, and long noncoding RNAs (lncRNAs) have been implicated in its tumourigenesis and progression. However, the roles lncRNAs play in lung cancer remain unclear. In this study, we discovered an important role for the lncRNA MNX1 Antisense RNA 1 (MNX1-AS1) as a critical regulator of one-carbon metabolism reprogramming. Glutamine depletion altered chromatin accessibility, leading to downregulation of MNX1-AS1, while elevated expression of MNX1-AS1 was correlated with poor prognosis in patients with non-small cell lung cancer. Functional studies showed that MNX1-AS1 promoted cell proliferation and sphere formation in vitro, and subcutaneous and orthotopic tumour growth in vivo. Mechanistically, MNX1-AS1 directly binds to calcyclin binding protein (CACYBP), protecting it from ubiquitin-mediated degradation; thus, the MNX1-AS1/CACYBP complex accelerates the transcription of key one-carbon metabolism-related genes through the Wnt/β-catenin pathway. MNX1-AS1/CACYBP/β-catenin axis upregulated key one-carbon metabolism-related genes, which were essential for generating related metabolites and maintaining cellular redox balance to support lung cancer cell proliferation. These findings established that the lncRNA MNX1-AS1 acts as a crucial driver of one-carbon metabolism reprogramming in non-small cell lung cancer and highlight that the newly identified MNX1-AS1/CACYBP/β-catenin axis may serve as a potential prognostic biomarker and therapeutic target for lung cancer intervention.

DOI: https://doi.org/10.1038/s41418-026-01825-3