bims-glucam 2026-09-20 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–09–20
24 papers selected by
Sreeparna Banerjee, Middle East Technical University

The role of glutamine metabolism in the pathogenesis of idiopathic pulmonary fibrosis and its therapeutic potential.
Glutamine Metabolism: a Metabolic Hub Linking Vascular Remodeling and Plaque Stability in Atherosclerosis.
Valproic acid inhibits glutamine uptake to induce ferroptosis in triple-negative breast cancer.
HGF/c-MET signaling induces glutamine metabolism in MET-amplified head and neck squamous cell carcinoma via MAPK/ERK-dependent induction of GLS-1.
Glutamine Metabolism-associated Molecular Heterogeneity and Prognosis in Pancreatic Adenocarcinoma.
Targeting the NEAT1/miR-23b-3p/Glutaminase Axis.
Metabolic reprogramming-related drug resistance in osteosarcoma: from molecular mechanisms to therapeutic translation.
In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity.
Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.
Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.
Hypercapnia Induces Mitochondrial Adaptations and Alters Glutamine Metabolism to Drive a Distinct Metabolic Phenotype in Monocytes.
Altered Glutamine/α-Ketoglutarate Metabolism Associates with Decidualization Defects in Recurrent Implantation Failure and is Ameliorated by α-Ketoglutarate Supplementation in Mice.
Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds.
Metabolic plasticity in castration-resistant prostate cancer: reprogramming mechanisms and therapeutic opportunities.
Metabolic regulation of tumor angiogenesis in colorectal cancer: mechanisms and therapeutic opportunities.
Glutamine metabolism as a rheostat of CD4+ T cell pathogenic function in metabolic dysfunction-associated steatotic liver disease.
Feeding Intolerance and Citrulline Generation Test in the Critically Ill: A Prospective Study.
Extracellular signal-regulated kinase 3 forms a nuclear complex with Aly/REF export factor and the splicing factor proline and glutamine rich to exacerbate pathological cardiac remodeling due to pressure overload.
Metabolic reprogramming and immune evasion interaction in the tumor microenvironment promote tumor progression.
Glutamine, a Potential Metabolomic Biomarker and Therapeutic Target in Radiation-induced Liver Damage.
Targeting tryptophan hydroxylase 1 restricts growth and suppresses plasticity in neuroendocrine prostate cancer.
Metabolic modulation of glioblastoma by dietary intervention: a systematic review.
Modulation of Ferroptosis Bridges Radiotherapy and Immunotherapy to Improve Cancer Treatment Outcomes.
Amino acid transporters in hepatocellular carcinoma: Gatekeepers of metabolic reprogramming.

Front Oncol. 2026 ;16 1873614

The role of glutamine metabolism in the pathogenesis of idiopathic pulmonary fibrosis and its therapeutic potential.

Junzi Li.

  Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease characterized by usual interstitial pneumonia, relentless decline in lung function and incomplete disease modification by available antifibrotic therapies. Beyond canonical profibrotic pathways, accumulating evidence identifies aberrant glutamine metabolism as a convergent metabolic feature of IPF pathogenesis. In structural cells, glutaminolysis fuels myofibroblast activation, de novo glycine and proline synthesis for collagen, whereas epithelial glutamine utilization may support antioxidant defence, mitochondrial adaptation and repair. In immune cells, glutamine shapes macrophage and T-cell polarization and may contribute to an inflammatory, profibrotic microenvironment. Glutamine-derived intermediates intersect with mTOR/AMPK and TGF-β/Smad signalling and act as cofactors for epigenetic regulators, thereby stabilizing apoptosis-resistant, profibrotic transcriptional programmes. Experimental models and human studies further demonstrate upregulation of glutamine transporters and glutaminase 1 (GLS1) in fibrotic lungs, protection from bleomycin-induced fibrosis after genetic or pharmacologic GLS1 inhibition, and a genetic association between lower circulating glutamine and increased IPF risk. Importantly, the effects of glutamine metabolism are context- and cell type-dependent: epithelial and immune glutamine utilization may support repair, barrier integrity and host defence, whereas excessive fibroblast-directed glutaminolysis promotes matrix accumulation. Building on these observations, this review synthesizes current knowledge on cell type-relevant glutamine metabolism in lung fibrosis, distinguishes direct lung-fibrosis evidence from extrapolated mechanistic evidence, delineates its integration with fibrogenic signalling, oxidative stress, mitochondrial stress and immunometabolism, and critically evaluates the therapeutic potential and caveats of targeting glutamine uptake, catabolism and nutrient-sensing pathways as adjuncts to existing antifibrotic regimens.

Keywords:  glutamine metabolism; glutaminolysis; idiopathic pulmonary fibrosis; immunometabolism; mTOR/AMPK; myofibroblast

DOI:  https://doi.org/10.3389/fonc.2026.1873614
Curr Atheroscler Rep. 2026 Sep 16. pii: 90. [Epub ahead of print]28(1):

Glutamine Metabolism: a Metabolic Hub Linking Vascular Remodeling and Plaque Stability in Atherosclerosis.

Jiangqin Wang, Jingwen Wang, Peng Gao, Jie Tian.

   PURPOSE OF REVIEW: Atherosclerosis (AS), the pathological basis of atherosclerotic cardiovascular disease (ASCVD), is a chronic, progressive inflammatory disease whose major clinical events are primarily caused by plaque rupture and subsequent thrombosis. Plaque stability is critically dependent on vascular remodeling and dynamic extracellular matrix (ECM) remodeling. Accumulating evidence suggests that metabolic reprogramming is a key regulator of vascular cell phenotypic transitions and plaque progression. Among various metabolic pathways, glutamine (Gln) metabolism is of particular interest because it links nutrient availability with vascular cell function through carbon and nitrogen supply, maintenance of redox homeostasis, and generation of metabolites involved in epigenetic regulation. However, the contribution of Gln metabolism to AS progression remains incompletely understood. This review summarizes current advances in Gln metabolism and discusses its regulatory roles in vascular remodeling and plaque stability, with a focus on its implications for AS pathogenesis and therapeutic strategies.
RECENT FINDINGS: Metabolomic, single-cell sequencing, and spatial transcriptomic studies have identified the role of Gln metabolism in regulating the functions of multiple vascular cell types, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), macrophages, and fibroblasts/myofibroblasts. Through glutaminolysis, Gln generates α-ketoglutarate (α-KG) to replenish the tricarboxylic acid (TCA) cycle, thereby influencing cellular proliferation, migration, inflammatory responses, and ECM remodeling. Furthermore, α-KG serves as an essential cofactor for α-KG-dependent dioxygenases, linking glutamine metabolism to epigenetic regulation through DNA and histone demethylation, ultimately influencing cell fate determination and pathological phenotypic switching. Glutamine metabolism may serve as an important metabolic regulator of vascular remodeling and plaque stability by linking metabolic, inflammatory, and epigenetic pathways. Targeting glutamine metabolism may represent a promising therapeutic strategy for stabilizing atherosclerotic plaques and preventing cardiovascular events. Further studies integrating multi-omics approaches and mechanistic validation are warranted to facilitate the clinical translation of glutamine metabolism-based interventions in AS.

Keywords:  Atherosclerosis; Endothelial cells; Fibroblasts/myofibroblasts; Macrophages; Vascular remodeling; Vascular smooth muscle cells; glutamine metabolism

DOI:  https://doi.org/10.1007/s11883-026-01466-4
Cell Signal. 2026 Sep 13. pii: S0898-6568(26)00549-8. [Epub ahead of print]149 112890

Valproic acid inhibits glutamine uptake to induce ferroptosis in triple-negative breast cancer.

Yisong Yang, Jiazhuo Liu, Yiting Liu, Teng Zou, Ran Tao, Xiaoyu Tan, Shuangping Liu.

   BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis. Metabolic reprogramming, particularly the addiction to glutamine, is a hallmark of TNBC. The glutamine transporter ASCT2 (SLC1A5) is crucial for sustaining this dependency. Valproic acid (VPA), a short-chain fatty acid derivative synthesized from succinic acid and naturally occurring in valerian, is an antiepileptic drug with HDAC inhibitory activity. Although VPA has been found to possess anticancer potential in recent years, with its key mechanism involving the metabolic reprogramming of tumor cells, the regulatory mechanism of its action on glutamine metabolism in triple-negative breast cancer (TNBC) remains unclear.
OBJECTIVE: This study aims to investigate whether VPA inhibits TNBC progression by disrupting glutamine uptake and promoting ferroptosis.
METHODS AND RESULTS: TNBC cell lines (MDA-MB-231 and BT-549) and a nude mouse xenograft model were employed. In vitro experiments demonstrated that VPA dose-dependently inhibited the viability, proliferation, and colony formation of TNBC cells, while exerting minimal effects on the regular breast epithelial cell MCF-10 A. Non-targeted metabolomics analysis revealed significant modulation of glutamine metabolism by VPA. Further experiments confirmed that VPA treatment markedly reduced cellular glutamine uptake and downregulated expression of the key glutamine transporter ASCT2. Mechanistically, VPA downregulates ASCT2, leading to reduced intracellular glutathione (GSH) synthesis, the accumulation of lipid-reactive oxygen species (ROS) and malondialdehyde (MDA), and the suppression of GPX4 expression-a key protein involved in ferroptosis-which ultimately induces ferroptosis. Treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or overexpression of ASCT2 reversed both VPA-induced ferroptosis and growth suppression. Depletion of ASCT2 (siRNA) mimics the effect of VPA, similarly inhibiting TNBC cell growth and inducing ferroptosis. In vivo experiments further confirmed that VPA treatment significantly inhibited tumor growth in mice, accompanied by a downregulation of ASCT2 and GPX4 protein levels. Conversely, ASCT2 overexpression similarly reversed the antitumor effects of VPA in vivo.
CONCLUSION: This study demonstrates that VPA exerts anti-TNBC effects by downregulating ASCT2, triggering a glutamine uptake crisis, and consequently inducing ferroptosis. This study unveils a novel mechanism of VPA through targeting glutamine metabolism and suggests its potential as a therapeutic strategy for TNBC by exploiting metabolic vulnerability.

Keywords:  ASCT2/SLC1A5; Ferroptosis; Glutamine metabolism; Triple-negative breast cancer; Valproic acid

DOI:  https://doi.org/10.1016/j.cellsig.2026.112890
Med Oncol. 2026 Sep 15. pii: 287. [Epub ahead of print]43(10):

HGF/c-MET signaling induces glutamine metabolism in MET-amplified head and neck squamous cell carcinoma via MAPK/ERK-dependent induction of GLS-1.

Marius Hörner, Florian Mersdorf, Natalie Burkard, Andreas Vollmer, Babak Saravi, Tobias Renner, Julian Volland, Alexander Kübler, Nicolas Schlegel, Stefan Hartmann.

  Head and neck squamous cell carcinoma (HNSCC) is a common malignancy characterized by poor survival due to recurrence, metastasis and therapy resistance. In addition to genetic alterations, metabolic reprogramming is a hallmark of HNSCC and contributes to tumor progression and treatment failure. The hepatocyte growth factor (HGF)/c-MET signaling pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), where it promotes tumor cell proliferation, invasion, and increased glucose metabolism. However, its contribution to the regulation of glutamine metabolism in HNSCC remains largely unexplored. Basal GLS-1 expression was compared between primary human oral keratinocytes (HOK) and HNSCC cell lines with distinct MET status (Detroit 562, FaDu, and SCC-154). Subsequently, HNSCC cell lines were stimulated with HGF, and GLS-1 expression was assessed by quantitative PCR and Western blotting. Functional effects were evaluated using wound-healing assays, enzymatic quantification of extracellular glutamine and glutamate, and Seahorse-based mitochondrial respiration analysis. GLS-1 was silenced using siRNA to determine its functional relevance. In addition, transcriptomic data from the TCGA-HNSC cohort were analyzed to evaluate the clinical association between MET signaling, MAPK/ERK pathway activity, and GLS1 expression. HGF stimulation selectively induced GLS-1 expression in MET-amplified Detroit 562 cells at both mRNA and protein levels, whereas MET wild-type cells remained largely unaffected. Mechanistically, HGF triggered robust ERK1/2 activation, and pharmacological inhibition of c-MET or ERK signaling abrogated GLS-1 induction. Functionally, HGF increased glutamine consumption, glutamate production, and mitochondrial respiratory capacity in a GLS-1-dependent manner, while GLS-1 silencing significantly impaired HGF-induced cell migration and mitochondrial respiration. Importantly, analysis of TCGA-HNSC tumors revealed significant correlations between MET expression, MAPK/ERK pathway activity, and GLS1 expression, supporting the clinical relevance of the identified signaling axis. Together, these findings identify GLS-1 as a downstream effector of HGF/c-MET-MAPK/ERK signaling in MET-amplified HNSCC and link oncogenic signaling to glutamine metabolism and mitochondrial function. The observed associations in TCGA patient tumors further support the clinical relevance of this pathway and suggest that targeting glutaminase or ERK signaling may represent a promising therapeutic strategy in c-MET-driven HNSCC.

Keywords:  Glutamine metabolism; HGF; HNSCC; MAPK/ERK; MET-signaling

DOI:  https://doi.org/10.1007/s12032-026-03409-0
Curr Med Chem. 2026 Sep 10.

Glutamine Metabolism-associated Molecular Heterogeneity and Prognosis in Pancreatic Adenocarcinoma.

Wenyu Li, Min Luo, Xuehong Wang, Yuqian Zhou.

   BACKGROUND: Pancreatic Adenocarcinoma (PAAD) is characterized by pronounced molecular heterogeneity and profound metabolic reprogramming. Glutamine metabolism plays a critical role in sustaining tumor growth and shaping the tumor microenvironment; however, its contribution to molecular heterogeneity, immune characteristics, and clinical outcomes in PAAD remains incompletely understood.
METHODS: We conducted an integrative transcriptomic analysis utilizing transcriptomic and clinical data from TCGA, GTEx, and an independent GEO cohort to focus on genes involved in glutamine metabolism. Unsupervised consensus clustering was performed to define molecular subtypes associated with glutamine metabolism. Differential expression analysis, pathway enrichment analysis, and established transcriptome-based methods were applied to characterize subtype-specific biological features. Using LASSO-- Cox regression, a prognostic risk model was created and validated in internal and external cohorts. Multilevel biological validation was further conducted using immunohistochemistry data, pancreatic cancer cell line profiles, and single-cell RNA sequencing resources.
RESULTS: Two reproducible glutamine metabolism-associated molecular subtypes were identified, exhibiting distinct survival outcomes and immune landscapes. The metabolically aggressive subtype was associated with increased immune evasion potential and enrichment of pathways related to cell cycle progression, hypoxia, and metabolic dysregulation. An eight-gene prognostic signature demonstrated stable predictive performance across cohorts and remained independently associated with overall survival. Protein-level expression and single-cell analyses further supported the biological relevance of key prognostic genes.
DISCUSSION: These findings suggest that glutamine metabolism-associated heterogeneity may contribute to immune modulation and clinical divergence in PAAD. The integration of metabolic stratification with immune landscape characterization provides a biologically coherent framework for understanding tumor progression and therapeutic resistance.
CONCLUSION: This study establishes a glutamine metabolism-centered integrative framework that links molecular heterogeneity with immune modulation and clinical outcomes in PAAD. The identified biomarkers and stratification strategy provide biologically interpretable insights and may facilitate metabolic-based risk stratification and personalized therapeutic decision-making in pancreatic adenocarcinoma.

Keywords:  Pancreatic adenocarcinoma; glutamine metabolism; molecular heterogeneity; prognostic biomarkers; tumor immune microenvironment

DOI:  https://doi.org/10.2174/0109298673488452260827110054
Int Heart J. 2026 Sep 11.

Targeting the NEAT1/miR-23b-3p/Glutaminase Axis.

Lin Li, Kun Jiang, Dong Pan.

  Oxidative stress-induced cardiomyocyte injury constitutes a pivotal pathogenic mechanism driving heart failure progression. Emerging evidence implicates lncRNA NEAT1 in cardiovascular pathophysiology. This study delineates the mechanistic cascade through which NEAT1 orchestrates redox adaptation via glutamine metabolic reprogramming. Using H2O2-treated H9c2 rat cardiomyocytes as an oxidative stress model, we identified dose-dependent NEAT1 upregulation concomitant with miR-23b-3p suppression. NEAT1 silencing or miR-23b-3p overexpression exacerbated oxidative vulnerability, manifested by elevated viability loss and apoptosis rate. Bioinformatic prediction coupled with RNA pulldown and dual-luciferase assays established NEAT1/miR-23b-3p ceRNA interaction. Sublethal oxidative stress triggered adaptive glutaminolysis activation characterized by elevated glutamine uptake and GLS activity. Luciferase assay validated miR-23b-3p directly targeted GLS 3'UTR, while metabolic rescue assays demonstrated GLS reconstitution reversed miR-23b-3p-mediated metabolic suppression and restored oxidative tolerance. Epistatic analysis confirmed NEAT1's cardioprotection requires miR-23b-3p/GLS axis modulation, with miR-23b-3p restoration abrogating NEAT1-overexpression benefits. These findings were further corroborated in an in vivo rat model of myocardial ischemia-reperfusion injury, which recapitulated the upregulation of NEAT1 and GLS, downregulation of miR-23b-3p, and enhanced glutaminase activity in the infarct risk zone. Collectively, these results suggest the existence of a novel NEAT1/miR-23b-3p/GLS regulatory axis governing redox-stress adaptation in both cellular and animal models.

Keywords:  Cardiomyocyte apoptosis; Glutamine metabolism; lncRNA-NEAT1

DOI:  https://doi.org/10.1536/ihj.25-248
Front Mol Biosci. 2026 ;13 1928880

Metabolic reprogramming-related drug resistance in osteosarcoma: from molecular mechanisms to therapeutic translation.

Qun Wu, Hongxiang Chen, Jian Li.

   Background: Osteosarcoma remains the most prevalent primary malignant bone tumor in adolescents and young adults. For patients with localized disease, 5-year overall survival reaches 60%-70%; however, for those with metastatic or recurrent disease, 5-year survival remains stagnant at approximately 20%, and chemoresistance represents the primary obstacle to improved outcomes.
Objective: This review systematically elucidates the crosstalk among glycolytic, lipid, and glutamine pathways and their synergistic interactions with the immune microenvironment in driving osteosarcoma drug resistance, while evaluating the translational potential of metabolic targeted therapies.
Results: We highlight that aerobic glycolysis-derived histone lactylation, which has been shown to activate multidrug resistance gene transcription in other cancers and represents a candidate epigenetic mechanism warranting investigation in osteosarcoma; SCD1-mediated monounsaturated fatty acid synthesis confers ferroptosis resistance; glutamine-derived α-KG supports epigenetic programming and redox homeostasis; and metabolic competition creates an immunosuppressive tumor microenvironment. We further discuss metabolic heterogeneity, plasticity, and metabolomic methodologies as applied to osteosarcoma.
Conclusion: Single-agent metabolic inhibitors show limited clinical efficacy due to metabolic plasticity and compensatory activation. Almost all metabolic targeting evidence remains preclinical; no metabolic therapy has yet entered standard osteosarcoma care. Triple combination strategies (metabolic inhibitors + immunotherapy + chemotherapy) represent a mechanistically attractive but clinically untested hypothesis. Telaglenastat (CB-839), a glutaminase inhibitor, has been prioritized for osteosarcoma clinical trials but efficacy data in osteosarcoma patients remain pending.

Keywords:  drug resistance; glutamine metabolism; glycolysis; lipid metabolism; metabolic reprogramming; osteosarcoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2026.1928880
Sci Immunol. 2026 Sep 18. 11(123): eaea4179

In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity.

Wenlong Jia, Guanxing Yu, Shenqi Han, Zhibo Ma, Junnan Liang, Wei Yan, Xinling Zhang, Chenglong Zeng, Lin Xue, Feng Xia, Ganxun Li, Ran Tao, Peixiang Lan, Wei Yan, Wanguang Zhang, Huifang Liang, Xiaoping Chen, Zhao Huang, Bixiang Zhang.

Tumor cells often evade immune pressure via metabolic reprogramming, yet the key metabolic regulators orchestrating this process remain incompletely defined. Here, using in vivo metabolic CRISPR screening under distinct immune pressures, we identified tumor cell-intrinsic solute carrier family 1 member 5 (SLC1A5) as a metabolic node that sustains an immunosuppressive tumor microenvironment. SLC1A5-mediated glutamine metabolism in tumor cells modulated CD8 T cell infiltration and effector function, reshaping tumor responses to immune checkpoint blockade therapy. Glucose deprivation up-regulated SLC1A5 isoforms in tumor cells, enhancing glutamine uptake and glutathione synthesis. This adaptation limited mitochondrial oxidative stress and cytosolic mitochondrial DNA release, thereby suppressing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, interferon-β production, and CD8 T cell antitumor responses. These findings define a glutamine-fueled metabolic program as a barrier to tumor immunogenicity, positioning SLC1A5 as a tumor-intrinsic metabolic regulator with potential therapeutic relevance.

DOI: https://doi.org/10.1126/sciimmunol.aea4179
Mol Biol Rep. 2026 Sep 18. pii: 1595. [Epub ahead of print]53(1):

Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.

Kaviya S, Sumathy Arockiasamy, K Satish Srinivas, Sundersingh Shirley.

  Metabolic reprogramming is a defining hallmark of CRC. The Warburg effect is the principal metabolic feature of CRC cells, wherein glucose is preferentially catabolized into lactate to sustain accelerated proliferation. In parallel, CRC cells exhibit strong glutamine reliance to replenish tricarboxylic acid (TCA) cycle intermediates required for adenosine triphosphate (ATP) production, lipid biosynthesis and redox homeostasis. Consequently, mitochondria play a central role in supporting the augmented biosynthetic and energetic demands beyond basal energy homeostasis. In this regard, the mitochondrial pyruvate carrier (MPC), mitochondrial citrate carrier (CIC) and the mitochondrial glutamine carrier (SLC1A5_var) located in the inner mitochondrial membrane, are emerging areas of investigation in CRC metabolism. MPC is frequently lost or downregulated in CRC, whereas CIC was found to be upregulated and promote CRC growth and survival. In contrast, SLC1A5_var has been reported to exhibit elevated expression in colon cancer cells. Recent evidence indicates that its inhibition reduces CRC cell viability; however, its specific role in CRC progression remains to be elucidated. Notably, these transporters may influence the metabolic-epigenetic landscape of CRC through metabolite-dependent regulation of chromatin and transcriptional processes. This review highlights current insights into mitochondrial metabolite transporters in CRC and their potential metabolic and epigenetic implications. Thus, elucidating the roles of these transporters may provide novel therapeutic strategies for CRC management.

Keywords:  Colorectal cancer; Metabolic reprogramming; Warburg effect; epigenetic; glutamine reliance; mitochondrial carriers

DOI:  https://doi.org/10.1007/s11033-026-12769-9
Nat Commun. 2026 Aug 15. pii: 9805. [Epub ahead of print]17(1):

Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.

Ya Chun Yu, Yulseung Sung, Seonghun Lim, Jeong Ah Kwon, Min Ju Lee, Hyeong Yun Kim, Sunghoon Kim, Kuglae Kim, Do Sik Min, Hee Chan Yoo, Jung Min Han.

Trained immunity enables innate immune cells to acquire memory-like responses, offering a strategy to enhance antitumor immunity. However, the metabolic‒epigenetic mechanisms underlying this process remain poorly defined. Here, we show that lipopolysaccharide-induced macrophage training is encoded by a mitochondrial metabolic checkpoint. Integrated transcriptomic, metabolomic, and epigenomic profiling reveals that TLR4-NF-κB signaling represses SLC1A5_var, a mitochondrial glutamine transporter, limiting glutaminolysis and reducing α-ketoglutarate availability. This metabolic restriction limits removal of the activating histone mark histone H3 lysine 4 trimethylation by KDM5B, thereby maintaining inflammatory gene accessibility. Functionally, pharmacological inhibition or myeloid-specific knockdown of SLC1A5_var potentiates macrophage training and improves tumor control in murine cancer models, whereas enforced SLC1A5_var expression or α-ketoglutarate supplementation abrogates these effects. These findings define an SLC1A5_var-α-ketoglutarate-KDM5B metabolic-epigenetic axis that programs macrophage trained immunity and illustrate how targeted metabolic restriction can be leveraged to enhance innate immune responses against cancer.

DOI: https://doi.org/10.1038/s41467-026-76757-0
Immunol Cell Biol. 2026 Sep 16.

Hypercapnia Induces Mitochondrial Adaptations and Alters Glutamine Metabolism to Drive a Distinct Metabolic Phenotype in Monocytes.

Ben Reddan, David E Phelan, Xiaofei Yin, Lorraine Brennan, Martina Wallace, Eoin P Cummins.

Carbon dioxide (CO2) is an ancient and ubiquitous physiological gas generated during aerobic respiration. Historically viewed as a simple metabolic waste product, CO2 has received far less research attention than oxygen (O2), the primary substrate of aerobic respiration. However, emerging evidence has revealed important roles for CO2 in immunometabolism, immunology, muscle physiology, and clinical medicine. While circulating pCO2 levels are tightly regulated, patients with lung diseases such as chronic obstructive pulmonary disease (COPD) frequently develop hypercapnia, pCO2 > 45 mmHg. Hypercapnia is associated with significantly increased mortality, higher risk of ICU admission, and a global prevalence estimated at 13-15 million patients. Its broader clinical consequences remain poorly understood and are inadequately integrated into current therapeutic paradigms. Here, we examined the impact of hypercapnia on the metabolic profile of monocytes. We demonstrate that 24 h of buffered hypercapnia induces a marked reduction in mitochondrial mass. This is accompanied by dysregulation of mitochondrial membrane potential and key bioenergetic substrates (NADH/NAD+ and ATP content). We further show that hypercapnia alters the abundance of metabolites and proteins associated with mitochondrial metabolism, with effects spanning glucose, glutamine, and lipid metabolism. Thus, we provide direct mechanistic evidence that hypercapnia directly alters the glutamine-glutamate-proline synthesis axis. Collectively, these findings establish the foundation for a discrete hypercapnic metabolic phenotype, that is, in several respects, distinct from the metabolic adaptations observed in hypoxia. We propose that hypercapnia triggers a cascade of metabolic adaptations with tissue-dependent consequences on cellular effector functions.

DOI: https://doi.org/10.1111/imcb.70162
Reproduction. 2026 Sep 10. pii: xaag116. [Epub ahead of print]

Altered Glutamine/α-Ketoglutarate Metabolism Associates with Decidualization Defects in Recurrent Implantation Failure and is Ameliorated by α-Ketoglutarate Supplementation in Mice.

Zimeng Zheng, Jialu Shi, Wenjie Zhou, Xiaoxiao Gao, Jun Shao, Li Wang, Tao Zhang, Mingqing Li.

  Endometrial decidualization is a critical determinant of embryo implantation, and disruption in this process can lead to implantation failure. While various metabolic pathways regulate decidualization, the detailed metabolic characteristics and the mechanisms behind this remain unclear. Here we identified that during the process of decidualisation, the concentrations of glutamine and α-ketoglutarate (α-KG) were significantly elevated. Impaired glutamine/α-KG metabolism disrupts decidualization and triggers metabolic reprogramming characterized by decreased oxidative phosphorylation and glycolysis, leading to defective trophoblast spheroid adhesion and spreading. Further analysis revealed glutamine/α-KG metabolic abnormalities in the endometrial tissue of patients with recurrent implantation failure (RIF). Notably, supplementation with α-KG promotes decidualization and improves pregnancy outcomes (i.e., implantation number and pregnancy rate) in mice with impaired glutamine/α-KG metabolism. Thus, our study highlights the glutamine/α-KG metabolic axis as a key player in RIF, offering a scientific rationale for innovative preventive and therapeutic approaches.

Keywords:  decidualization; glutamine; recurrent implantation failure; α-ketoglutarate

DOI:  https://doi.org/10.1093/reprod/xaag116
J Nanobiotechnology. 2026 Jul 28. pii: 859. [Epub ahead of print]24(1):

Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds.

Yue Zhang, Fei Han, Yixuan Yuan, Mengyang Li, Linbin Yi, Yujie Xiao, Dongliang Zhang, Zhi Zhang, Yunchuan Wang, Hongtao Wang, Dahai Hu.

  Chronic diabetic wounds are trapped in a persistent inflammatory state, largely due to macrophage failure to transition from pro-inflammatory (M1) to pro-reparative (M2) phenotypes. Here, we show that adipose-derived stem cell extracellular vesicles (ADSC-EVs) deliver functional mitochondria into diabetic wound macrophages, thereby restoring tricarboxylic acid (TCA) cycle-driven M2 polarization. Mechanistically, ADSC-EV-mediated mitochondrial transfer reactivates pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), increases TCA cycle flux, and suggests enhanced glutamine anaplerosis, as evidenced by ¹³C-glucose isotope tracing. This metabolic rewiring restores oxidative phosphorylation (OXPHOS), elevates oxygen consumption rate (OCR) and suppresses glycolysis. Consequently, ADSC-EV treatment reduces M1 macrophages and increases M2 macrophages, lowers pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, MCP1, p < 0.0001), and upregulates IL-10 in vitro, p < 0.0001). In a diabetic mouse wound model, a single course of ADSC-EVs accelerates wound closure at day 14 (p < 0.05), enhances re-epithelialization and collagen deposition, and reduces local oxidative stress and inflammation. Mitochondria‑depleted Rho-ADSC-EVs show markedly diminished effects, confirming that functional mitochondrial transfer is the primary driver. Our findings establish ADSC-EV-mediated mitochondrial transfer as a central metabolic reprogramming strategy that breaks the inflammatory lock in diabetic wounds and promotes healing.

Keywords:  ADSC-EVs; Diabetic wound; Macrophages; Metabolic remodeling; Mitochondrial transfer; TCA cycle

DOI:  https://doi.org/10.1186/s12951-026-04846-9
Cell Signal. 2026 Sep 12. pii: S0898-6568(26)00544-9. [Epub ahead of print]149 112885

Metabolic plasticity in castration-resistant prostate cancer: reprogramming mechanisms and therapeutic opportunities.

Yanzhi Lou, Zhengda Lou, Luo He, Junfeng Luo.

  Prostate cancer (PCa) is one of the most common malignant tumors, and most patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Metabolic plasticity, which allows cancer cells to reprogram glucose, lipid, and glutamine utilization, plays a key role. This metabolic adaptation meets the bioenergetic and biosynthetic needs of tumor cells, and it can interact with the androgen receptor (AR) signaling pathway bidirectionally to evade immune surveillance via metabolic reprogramming. Current treatments include single metabolic node inhibition and AR-guided combination therapy. However, due to intratumoral metabolic heterogeneity, compensatory pathway activation, and systemic metabolic toxicity of drugs, there is a need to explore new intervention targets and strategies. This article comprehensively discusses the metabolic network, regulatory mechanism, and current challenges of CRPC in order to provide a theoretical basis for clinical prevention and treatment.

Keywords:  Castration-resistant prostate cancer; Metabolic plasticity; Metabolic reprogramming; Prostate cancer; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.cellsig.2026.112885
Biochim Biophys Acta Rev Cancer. 2026 Sep 12. pii: S0304-419X(26)00185-X. [Epub ahead of print]1881(6): 189713

Metabolic regulation of tumor angiogenesis in colorectal cancer: mechanisms and therapeutic opportunities.

Donghao Tang, Qijie Li, Costanza Tacchi, Marta Banchi, Guido Bocci.

  Colorectal cancer (CRC) progression is closely linked to abnormal vascular remodeling. Tumor vessels are structurally disorganized and poorly perfused, creating spatially heterogeneous regions of hypoxia and nutrient deprivation. These conditions reshape tumor metabolism by increasing glycolysis, glutamine utilization, and lipid metabolic plasticity. Metabolic changes, in turn, alter endothelial function and the surrounding tumor microenvironment through lactate accumulation, lipid-derived mediators, amino acid metabolism, and extracellular vesicle-mediated signaling. This reciprocal interaction contributes to vascular instability, impaired drug delivery, immune suppression, and treatment resistance. The VEGF pathway remains the principal therapeutic target in CRC angiogenesis. However, the benefits of anti-VEGF agents are often temporary because tumors activate alternative vascular programs and adapt metabolically to reduced blood supply. Hypoxia-induced HIF signaling is central to this response, but resistance also involves enhanced glycolysis, redox adaptation, lipid remodeling, amino acid metabolism, and communication among tumor, endothelial, stromal, and immune cells.In this review, we examine how metabolic reprogramming regulates angiogenesis in CRC and how vascular dysfunction, in turn, shapes tumor metabolism. We focus on endothelial metabolism, the glycolysis-lactate axis, amino acid and lipid metabolism, vitamin- and cofactor-dependent pathways, and exosomal non-coding RNAs. We also discuss how these mechanisms contribute to resistance to anti-angiogenic therapy and assess the rationale for combining vascular and metabolic interventions. A better understanding of this metabolic-vascular interaction may help identify more durable therapeutic strategies for CRC.

Keywords:  Anti-angiogenic therapy; Colorectal cancer; HIF-1α; Metabolic reprogramming; Tumor angiogenesis; VEGF

DOI:  https://doi.org/10.1016/j.bbcan.2026.189713
Cell Metab. 2026 Sep 18. pii: S1550-4131(26)00370-0. [Epub ahead of print]

Glutamine metabolism as a rheostat of CD4+ T cell pathogenic function in metabolic dysfunction-associated steatotic liver disease.

Keisuke Sawada, Jarren R Oates, Masaki Kimura, Traci E Stankiewicz, John Eom, Pablo C Alarcon, Hak Chung, Michelle S M A Damen, Cassidy J Ulanowicz, Jennifer L Wayland, Ethan S O Williams Fonner, Colin C Anderson, Hayde K Cuervo-Jimenez, Amelia M Pearson, Yunguan Wang, Nathan Salomonis, Ty D Troutman, Julie A Reisz, Jeffrey C Rathmell, Sara Szabo, Michael A Helmrath, Takanori Takebe, Maria E Moreno-Fernandez, Senad Divanovic.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) severity is independently linked with pathogenic CD4+ T cell responses and skewed hepatic glutamine (Gln) metabolism. Whether these processes interact to drive disease progression remains unclear. Here, we identify hepatic Gln depletion as a key feature of steatohepatitis that is linked with increased hepatic CD4+ T cell inflammation and hepatocellular damage in humans. In complementary mouse models, both total hepatic and hepatic CD4+ T cell Gln levels were similarly reduced. Restoration of hepatic Gln through supplementation selectively restrained hepatic CD4+ T cell inflammatory programs and alleviated hepatocellular damage and disease severity. Mechanistically, T cell-intrinsic Gls1-mediated glutaminolysis limited O-GlcNAcylation to dampen pathogenic CD4+ T cell inflammation. Importantly, Gln treatment dampened CD4+ T cell-mediated injury in human liver organoids. Together, these findings establish hepatic CD4+ T cell-intrinsic Gln metabolism as a critical rheostat of pathogenic inflammation in MASLD and invoke metabolism-targeted strategies to restrict disease progression.

Keywords:  MASH; MASL; MASLD; NAFL; NAFLD; NASH; adaptive immunity; amino acid metabolism; immunometabolism; obesity

DOI:  https://doi.org/10.1016/j.cmet.2026.08.018
Nutrients. 2026 Aug 24. pii: 2759. [Epub ahead of print]18(17):

Feeding Intolerance and Citrulline Generation Test in the Critically Ill: A Prospective Study.

Chloé Hild, Thibault Vieille, Marc Puyraveau, Hadrien Winiszewski, Karena Moretto Riedweg, Gaël Piton.

  Background/Objectives: Early feeding intolerance (FI) affects 20-50% of critically ill patients receiving enteral nutrition, yet no validated predictive tool exists and diagnosis remains retrospective. Plasma citrulline, mainly synthesized by enterocytes, is considered as the "factor V of the intestine". The citrulline generation test (CGT) evaluates small bowel mucosal function by measuring the increase in plasma citrulline after glutamine administration. We hypothesized that patients with a lower CGT would be more prone to FI. We aimed to compare CGT results according to the presence or absence of FI and to identify factors associated with CGT. Methods: This prospective study was conducted in the medical intensive care unit (ICU) of Besancon Hospital. Plasma citrulline and glutamine concentrations were measured at admission and after an alanine-glutamine dipeptide bolus. CGT was defined as the slope between basal and 90 min peak plasma citrulline concentrations. Signs of FI were collected during follow-up. Results: Among the sixty-six included patients, nine (14%) developed FI by day three, only characterized by vomiting and gastric residual volumes above 500 mL; abdominal pain or diarrhea were not observed. CGT values did not differ between patients with and without FI. CGT correlated positively with baseline citrulline and peak glutamine concentrations. Conclusions: FI was not associated with CGT, possibly because FI was predominantly gastric rather than intestinal. Low CGT values were associated with low plasma citrulline concentrations, suggesting reduced functional enterocyte mass. The positive correlation between CGT and peak plasma glutamine suggests that CGT not only reflects enterocyte function but also glutamine bioavailability.

Keywords:  citrulline generation test; critically ill; feeding intolerance

DOI:  https://doi.org/10.3390/nu18172759
Mol Biomed. 2026 Sep 18. pii: 177. [Epub ahead of print]7(1):

Extracellular signal-regulated kinase 3 forms a nuclear complex with Aly/REF export factor and the splicing factor proline and glutamine rich to exacerbate pathological cardiac remodeling due to pressure overload.

Wen-Ying Zhou, Feng Wang, Shu-Yu Wang, Li-Guo Wang, Ai-Qun Chen, Haoyue Tang, Ya-Peng Chen, Huan Zhang, Xiao-Fei Gao, Juan Zhang, Shao-Liang Chen, Jun-Jie Zhang.

  Pathological cardiac remodeling is a significant contributor to heart failure and mortality. Studies have demonstrated that extracellular signal regulated kinase 3 (ERK3) in cardiac fibroblasts aggravates pressure overload-evoked pathological cardiac remodeling via mitogen activated protein kinase-activated protein kinase-5 (MK5). However, myocardial ERK3 does not activate MK5, thus the role of myocardial ERK3 remains unclear. Through in vivo and in vitro experiments, we revealed that myocardial ERK3 expression increases under pressure overload and the protein accumulates significantly in the nucleus. Using cardiomyocyte-specific Erk3-deficient mice, neonatal rat cardiomyocytes and adult mouse cardiomyocytes, we found that cardiomyocyte-specific Erk3 deficiency ameliorated pressure overload-induced pathological cardiac remodeling in vivo. Co-immunoprecipitation, mass spectrometry, and single nucleus RNA sequencing were used to analyse for the nuclear translocation and downstream signaling mechanisms of ERK3. Specifically, pressure overload enhances the binding of Aly/REF export factor (ALY) to ERK3, resulting in the truncation of the ERK3 C-terminal and its subsequent nuclear translocation to activate the thioredoxin-interacting protein (TXNIP)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway through the expression of the splicing factor proline and glutamine rich (SFPQ). To screen for targeted drugs, we conducted a virtual screening and identified estrone sulfate as an inhibitor of ALY to counteract hypertrophic effects. Collectively, our findings indicate that estrone sulfate functions as a novel inhibitor of the ALY-ERK3 signaling pathway, potentially serving as a promising therapeutic candidate for the management of pathological cardiac remodeling.

Keywords:  ALY; ERK3; Estrone sulfate; Nuclear transportation; Oxidative stress; Pathological cardiac remodeling

DOI:  https://doi.org/10.1186/s43556-026-00563-9
Front Oncol. 2026 ;16 1896937

Metabolic reprogramming and immune evasion interaction in the tumor microenvironment promote tumor progression.

Hailun Wang, Hanyu Zhao, Xuelu Pu, Yandu He, Yajun Li.

  Emerging evidence demonstrates that tumor metabolic reprogramming not only supports tumor-cell proliferation but also promotes the establishment of an immunosuppressive tumor microenvironment (TME) by altering nutrient competition and metabolite accumulation. Therefore, metabolic reprogramming and immune evasion should be regarded as closely interconnected processes rather than independent phenotypes. By altering the metabolite composition of the TME and local metabolic programs, tumor metabolic reprogramming suppresses immune activation and shapes immune-cell function and fate, thereby promoting cancer immune evasion. This review focuses on two mechanistically developed axes linking tumor metabolism to immune suppression: glycolysis-associated lactate accumulation and lactylation, and nutrient competition involving amino acids and lipids. We summarize how lactate acts as both a metabolic substrate and signaling mediator, how lactylation translates metabolic changes into epigenetic regulation of immune-related transcriptional programs, and how depletion of glutamine, tryptophan, and arginine, together with lipid accumulation and remodeling, impairs effector-cell metabolic fitness while favoring regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. We further examine hypoxia as a contextual amplifier, the immune-evasion outcomes and reciprocal feedback circuits produced by these alterations, and therapeutic strategies targeting the metabolism-immunity axis. Particular attention is given to context-dependent effects and evidence maturity, because lactate-, hypoxia-, and metabolite-associated pathways are not uniformly immunosuppressive across cell types and conditions. Although preclinical findings support interventions targeting lactate production or transport, lactylation-associated regulators, amino acid metabolism, and the ecto-5'-nucleotidase (CD73)-adenosine axis, clinical evidence remains limited and heterogeneous. Biomarker-guided patient selection, confirmation of target engagement, preservation of immune-cell metabolic fitness, and rational combination strategies will be essential for clinical translation.

Keywords:  clinical translation; combined therapy; immune evasion; immunosuppressive microenvironment; metabolic reprogramming; metabolism-immunity axis; tumor microenvironment; tumor progression

DOI:  https://doi.org/10.3389/fonc.2026.1896937
Radiat Res. 2026 Sep 04. pii: eRADE-25-00236.1. [Epub ahead of print]

Glutamine, a Potential Metabolomic Biomarker and Therapeutic Target in Radiation-induced Liver Damage.

Liming Gu, Yang Jiao, Wei Mo, Wenli Wang, Xiedong Hong, Shihong Li, Jianping Cao, Chang Wang.

Radiation-induced liver damage (RILD) significantly limits the clinical application of radiotherapy for upper abdominal malignancies. Radiation can induce metabolic disorder in liver tissues. However, there is no systematic research on the effects of radiation on liver metabolism. In this study, we collected time-series liver tissue samples from irradiated rats at multiple time points, from 3 days to 4 weeks after exposure, to reveal dynamic alterations in metabolic profiles throughout RILD progression. Acetylcholic acid, p-hydroxyphenyl-lactic acid, ascorbic acid, daidzein, and glutamine (Gln) were identified as potential biomarkers, demonstrating good diagnostic sensitivity and specificity. As a metabolomic biomarker, Gln emerged as a potential metabolic target based on pathway enrichment analysis, which could modulate the radiosensitivity of both mouse (JS-1) and human (LX-2) hepatic stellate cells. Transcriptomics, co-immunoprecipitation (Co-IP) and functional rescue experiments demonstrated that the regulation of radiosensitivity by Gln is mediated through the Col1α2/ITGB1/AKT signaling axis. In the mouse RILD model, Gln prevented irradiation-induced body weight loss, preserved liver structure, and reduced TGF-β and TNF-α expression as well as collagen deposition. L-alanyl-glutamine (Ala-Gln) and liposomes were introduced to further enhance the radioprotective effects of Gln. This study provides the necessary theoretical and experimental basis for diagnosis and intervention of RILD.

DOI: https://doi.org/10.1667/RADE-25-00236.1
J Clin Invest. 2026 Sep 17. pii: e200391. [Epub ahead of print]

Targeting tryptophan hydroxylase 1 restricts growth and suppresses plasticity in neuroendocrine prostate cancer.

Jing Wei, Jing Wang, Jingrui Chen, Michelle Zhang, Chia-Hui Chen, Tianjie Pu, Alivia O'Brien, Sephtis Hargrove, Eva Corey, Tzu-Ping Lin, Allen C Gao, Boyang Jason Wu.

  Advanced prostate cancer has increasingly developed a lethal neuroendocrine form, small cell/neuroendocrine prostate cancer (NEPC), as a consequence of the widespread use of highly potent androgen receptor signaling inhibitors in castration-resistant disease. The molecular mechanisms remain unclear and no effective therapies currently exist. We report that tryptophan hydroxylase 1 (TPH1), the enzyme responsible for peripheral serotonin biosynthesis - a neurotransmitter enriched in neuroendocrine tumors and a classical neuroendocrine biomarker - was upregulated in both de novo and therapy-induced human NEPC. TPH1 upregulation was necessary and sufficient for neuroendocrine differentiation and the NEPC phenotype through its enzymatic activity. Silencing TPH1 suppressed neuroendocrine plasticity and various aggressive behaviors of NEPC cells, including proliferation, invasion, sphere formation, and NEPC tumor xenograft growth. Mechanistically, TPH1 activated mTOR via intracellular serotonin-dependent serotonylation of mTOR at glutamine 2453, which triggered the induction of FOXM1 and E2F1 to drive NEPC differentiation and growth. Importantly, pharmacological inhibition of TPH1 using the clinically available inhibitor LX1606 effectively restricted growth and neuroendocrine marker expression in multiple NEPC cell lines and patient-derived xenografts. Collectively, these findings characterize TPH1's contribution to NEPC and suggest TPH1 as a potential therapeutic target.

Keywords:  Cell biology; Drug therapy; Oncogenes; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI200391
J Neurooncol. 2026 Sep 18. pii: 90. [Epub ahead of print]179(3):

Metabolic modulation of glioblastoma by dietary intervention: a systematic review.

Maged T Ghoche, Kenji Miki, Fanen Yuan, Megan Mantica, Sameer Agnihotri, Samuel K McBrayer, Kalil G Abdullah.

   OBJECTIVE: To systematically evaluate and critically synthesize preclinical and clinical evidence on the efficacy, safety, mechanistic rationale, and interpretive limitations of ketogenic diet (KD) and methionine restriction (MR) in glioma treatment.
METHODS: We systematically searched PubMed and Embase from inception through August 19, 2026, for in vivo preclinical and clinical studies evaluating KD or MR in glioma Clinical studies were eligible with or without a non-diet comparator because most available studies were early-phase, single-arm feasibility investigations. We extracted intervention, comparator, concurrent oncologic treatment, metabolic, safety, feasibility, and outcome data; assessed risk of bias using design-appropriate tools; and conducted narrative and structured direction-of-effect syntheses.
RESULTS: A total of 43 eligible reports were included: 14 preclinical and 18 clinical KD reports and 9 preclinical and 2 clinical studies of MR. Preclinical effects were heterogeneous: several diet-only experiments reduced growth or prolonged survival, whereas others showed limited activity; selected combinations with radiation, antiangiogenic therapy, glutamine targeting, or immune modulation produced greater effects. Clinical evidence primarily supported feasibility and metabolic activity, not independent efficacy, because most studies were small, uncontrolled, and confounded by concurrent or prior treatment. MR showed preclinical activity, but clinical evidence remained limited to two small chemotherapy-combination trials.
CONCLUSION: KD and MR have biologic rationale and can alter systemic or intratumoral metabolism, but current clinical data do not establish an independent survival benefit. Their effects cannot be separated reliably from surgery, radiotherapy, chemotherapy, bevacizumab, corticosteroids, and other co-interventions in most studies. Randomized trials with intention-to-treat analysis, standardized glucose-ketone index reporting, treatment and corticosteroid documentation, and longitudinal nutritional assessment are required before these diets can be recommended as effective glioma therapy.

Keywords:  Dietary intervention; Glioblastoma; Glioma metabolism; Ketogenic diet; Metabolic therapy; Methionine restriction

DOI:  https://doi.org/10.1007/s11060-026-05779-x
Cancer Lett. 2026 Sep 15. pii: S0304-3835(26)00572-0. [Epub ahead of print] 218808

Modulation of Ferroptosis Bridges Radiotherapy and Immunotherapy to Improve Cancer Treatment Outcomes.

Hong-Xiang Zhao, Xue Gao, Ru Xie, Miaoqing Zhao.

  Programmed cell death evasion fuels malignant progression and undermines therapeutic efficacy across diverse neoplasms. Ferroptosis, an iron-driven membrane lipid oxidation that culminates in catastrophic membrane integrity loss, has emerged as a metabolically distinct liability amenable to therapeutic exploitation through radiotherapy and immunotherapy combinations. Ionizing radiation overwhelms cellular antioxidant buffering capacities within the tumour microenvironment, shifting the redox balance toward peroxidative membrane injury and bypassing resistance mechanisms active in treatment refractory tumours. Ferroptotic corpses release alarmins and lipid peroxidation products, triggering immunogenic cell death that reshapes immune surveillance, draws in antigen presenting cells, and reduces activation barriers for immune checkpoint inhibitors and adoptive cellular therapies. At the same time, radiotherapy triggered metabolic reprogramming of the tumour microenvironment marked by glutamine dependence, lipid peroxidation accumulation, and cystine limitation aligns with immunomodulatory effects to strengthen anti-tumour immunity. This Review deconstructs the enzymatic cascades and metabolic checkpoints that govern ferroptotic vulnerability, mapping how radiation induced metabolic rewiring links cytotoxic and immune stimulatory therapeutic goals. We examine whether ferroptosis serves as a central node connecting radiotherapy and immunotherapy, assessing preclinical data on radio immunotherapy combination strategies that leverage this dual functionality. Translational barriers remain. Constrained therapeutic windows, lack of validated pharmacodynamic markers, and unclear toxicological consequences in normal tissues require careful evaluation prior to clinical application. We outline a conceptual framework for deploying ferroptosis as a mechanistic bridge between radiotherapy and immunotherapy, suggesting that its targeted induction under tumour specific metabolic conditions could reshape multimodal treatment strategies and enhance cancer treatment outcomes beyond the marginal gains achievable with single agent approaches.

Keywords:  Ferroptosis; immunotherapy; metabolic reprogramming; radiotherapy; tumour microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2026.218808
Mol Biol Rep. 2026 Sep 16. pii: 1582. [Epub ahead of print]53(1):

Amino acid transporters in hepatocellular carcinoma: Gatekeepers of metabolic reprogramming.

Joys Rachel Immanuel, Zioni Sangeetha Shankaran, Maheswaran Mani, Solomon F D Paul, Ben S Ashok, Leena Chand, Charles Emmanuel Jebaraj Walter.

  Hepatocellular carcinoma (HCC), an aggressive cancer predisposed to notable metabolic alterations, including an imbalance in amino acid transporters, remains a global concern. Amino acid transporters such as proton-assisted amino acid transporter (PAT), sodium-coupled neutral amino acid transporter (SNAT), cysteine/glutamate transporter (xCT), L-type amino acid transporter (LAT1), and Alanine-serine-cysteine transporter 2 (ASCT2). The tumour microenvironment (TME), cellular signalling pathways, tumour survival, and proliferation all depend heavily on these transporters. Current investigation of these transporters is fundamental in regulating the imbalance. Emerging therapeutics, including RNA-based therapeutics, small-molecule inhibitors and combinational treatment strategies with dietary intervention in metabolic reprogramming and oncological signalling are also discussed. The emergence of problems like tumour heterogeneity, transporter redundancy, off-target toxicity, and resistance mechanisms is substantial, even with available treatment options. A thorough understanding of amino acid transporters in HCC, including their emerging functions, might reveal metabolic vulnerabilities that could inform creative treatments for better outcomes.

Keywords:  Hepatocellular carcinoma; L-type amino acid transporter; amino acid transporters; and Alanine-serine-cysteine transporter 2; cysteine/glutamate transporter; proton-assisted amino acid transporter; public health

DOI:  https://doi.org/10.1007/s11033-026-12759-x