bims-glucam 2026-05-17 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–05–17
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Senescent Stroma-Derived Glutamine: A Driver of Aggressiveness in Prostate and Ovarian Cancer Cells.
Metabolic pattern changes of macrophages during cancer development and progression.
Small Molecule Inhibition of VDAC1 Reroutes Mitochondrial Metabolite Flux.
Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.
Wubie Fanchun Formula-inducible metabolites in primary ovarian insufficiency model mice that facilitate ovarian renovation.
Plant-Derived Modulators of Tumor Metabolism as Novel, Efficacious, and Low-Toxicity Therapeutic Agents for Cancer Treatment.
Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
Normoxic HIFα-mediated metabolic rewiring in cancer as a novel therapeutic target of tumor heterogeneity.
Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice.
Nuclear Magnetic Resonance-Based Metabolomic Profiling in Fibromyalgia Patients.
Amino Acid-Driven Mitochondrial Metabolic Rewiring Controls Antitumor Immunity.
Sex-specific systemic and brain metabolic responses to a standardized ketogenic diet in mice.
Sijunzi Decoction Reverses Metabolic Adaptation and Induces Ferroptosis in Cisplatin-Resistant Non-small Cell Lung Cancer: An Integrative Metabolomics-Pharmacology Analysis.
The metabolic effects of post-sepsis feeding of meals with only essential amino acids.
Glioblastoma cells utilize evolutionarily adapted cell metabolism to promote their malignant proliferation.
Reprogramming regulatory T cell plasticity for cancer immunotherapy.
Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.
Amino acid metabolism at the senescence-cancer interface.

Cells. 2026 Apr 24. pii: 770. [Epub ahead of print]15(9):

Senescent Stroma-Derived Glutamine: A Driver of Aggressiveness in Prostate and Ovarian Cancer Cells.

Giulia Lori, Caterina Mancini, Caterina Paffetti, Dayana Desideri, Erica Pranzini, Alice Santi, Manuela Leri, Alessio Biagioni, Matteo Benelli, Pietro Spatafora, Fedele Maria Manicone, Flavia Sorbi, Angela Leo, Massimiliano Fambrini, Sergio Serni, Francesca Magherini, Maria Letizia Taddei.

  Cancer progression is influenced by the dynamic interplay between tumor cells and the surrounding stromal microenvironment. Therapy-induced senescence (TIS) of stromal fibroblasts represents a common outcome of anticancer treatments, contributing to tumor progression through the senescence-associated secretory phenotype (SASP). While SASP cytokines promote cancer malignancy, the contribution of secreted metabolites from senescent cells remains poorly understood. Here, we investigate the role of senescent stromal metabolism in regulating prostate and ovarian cancer cell invasion. Conditioned media (CM) from TIS-induced human prostate (HPFs) and ovarian fibroblasts (HOFs) promote enhanced invasion of cancer cells. Invasion is partially preserved after exposure to boiled CM, suggesting a role for heat-stable metabolic factors. Metabolomic profiling of senescent fibroblasts-derived CM reveals a significant increase in Glutamine (Gln) levels, identifying senescent stromal fibroblasts as a previously unrecognized source of extracellular Gln in the tumor microenvironment (TME). Exposure of cancer cells to senescent CM increases Gln uptake, together with upregulation of the transporter SLC1A5 and increased intracellular Gln. This metabolic adaptation is associated with increased malignant phenotype including epithelial-to-mesenchymal transition (EMT) and stemness features. Extracellular Gln depletion, pharmacological inhibition of glutaminase-1 (GLS1) in cancer cells, or Gln synthetase (GS) silencing in fibroblasts markedly impair senescent fibroblasts CM-induced invasion, EMT markers expression, and stemness features in cancer cells. Stromal-derived Gln is associated with increased cancer cell invasion through activation of a redox-dependent NRF2/ETS1 signaling axis. Analysis of patient-derived transcriptomic datasets further suggests chemotherapy-associated upregulation of Gln metabolism and ETS1 expression. These findings identify senescent stromal-derived Gln as a key metabolic driver of prostate and ovarian cancer aggressiveness and reveal a TIS-associated metabolic vulnerability that could be explored in future preclinical studies.

Keywords:  NRF2/ETS1 signaling; cancer cell invasion; fibroblasts; glutamine metabolism; therapy-induced senescence

DOI:  https://doi.org/10.3390/cells15090770
J Transl Med. 2026 May 12.

Metabolic pattern changes of macrophages during cancer development and progression.

Guanfu Liu, Binxue Wang, Shaojie Wang, Shi Li, Hua Han, Tai An.

   BACKGROUND: Tumor-associated macrophages (TAMs) are critical components of the immune cell population within the tumor microenvironment (TME), where they play dynamic and multifaceted roles throughout the progression of tumorigenesis. Recent evidence suggests that shifts in macrophage metabolic programs-including glycolysis, oxidative phosphorylation, fatty acid utilization, glutamine metabolism, and the pentose phosphate pathway, are closely associated with diverse and context-dependent functional states rather than fixed polarization phenotypes. During tumor progression toward invasion and metastasis, macrophage metabolic programs dynamically adapt to spatial and temporal variations within the TME, often contributing to immunoregulatory or tumor-supportive niches that facilitate angiogenesis, tumor dissemination, immune evasion, and metabolic crosstalk with tumor cells. However, the precise mechanisms underlying these context-dependent adaptations remain incompletely understood.
MAIN BODY: This article reviews current evidence regarding TAM activation states and metabolic reprogramming by various signals in the TME during tumorigenesis and tumor progression, as well as dynamic alterations in TAM metabolic patterns. Furthermore, we explore how secondary metabolites present in the TME influence macrophage metabolic reprogramming and summarize current research on potential therapeutic agents targeting macrophage metabolism.
CONCLUSIONS: We propose that modulating key metabolic regulators in TAMs or intervening in metabolic-immune crosstalk pathways may offer novel strategies for precision medicine in cancer therapy, providing a theoretical foundation for metabolic intervention-based immunotherapeutic approaches.

Keywords:  Cancer immunotherapy; Immunometabolism; Metabolic intermediates; Metabolic reprogramming; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12967-026-08210-1
Mol Cells. 2026 May 13. pii: S1016-8478(26)00060-9. [Epub ahead of print] 100369

Small Molecule Inhibition of VDAC1 Reroutes Mitochondrial Metabolite Flux.

Seyed Majed Modaresi, Leilei Zhang, Amir Ata Saei, Morris Degen, Mohammad Khavani, Hassan Gharibi, Ákos Végvári, Zhiwei Ye, Jie Zhang, Evgeny Pavlov, Elizabeth A Jonas, Kenneth D Tew, Sebastian Hiller, Danyelle M Townsend, Eduardo N Maldonado.

  Voltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. NADH closes VDAC by binding to a pocket, conserved in all isoforms, located in the inner wall of the channel. Previously, we identified the small molecule SC18 that targets the NADH-binding pocket of VDAC1 employing computational analysis. Here, we explored the interaction between SC18 and VDAC1 using High-resolution Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations. Atomically resolved data precisely confirmed the computational results, showing that SC18 binds to a site on VDAC1 that partially overlaps with the NADH binding pocket. SC18, in the presence of NADH blocked the conductance of VDAC1 reconstituted in lipid bilayers. To determine the metabolic effect of SC18, we combined readouts of mitochondrial metabolism and glycolysis with functional metabolomics and proteomics. Short-term treatment with SC18 inhibited mitochondrial metabolism and ATP production. Treatment over 24 h and 48 h further reduced mitochondrial uptake of pyruvate and glutamine, utilization of tricarboxylic acid cycle intermediates, as well as lipid, DNA and amino acid synthesis. Concomitant with the inhibition of mitochondrial metabolism, cellular uptake of glucose and glutamine increased in parallel with augmented lactate release. These results indicate that compensatory enhanced glycolysis sustains ATP production after impaired mitochondrial function induced by SC18 blockage of VDAC1. Our work set a mechanistic foundation for VDAC1 inhibition as a novel strategy to target and reprogram cancer metabolism through modulation of the biosynthetic ability of mitochondria.

Keywords:  SC18; VDAC1; cancer metabolism; glycolysis; mitochondria

DOI:  https://doi.org/10.1016/j.mocell.2026.100369
J Biol Chem. 2026 May 14. pii: S0021-9258(26)02022-3. [Epub ahead of print] 113150

Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.

Chengmeng Jin, Siying Zeng, Hao Wu, Xun Hu.

  Intracellular lactic acidosis, a metabolic state newly defined in this study, is characterized by a coupled increase in intracellular lactate and proton concentrations, resulting in higher levels inside cancer cells than outside. This finding expands the Warburg paradigm: lactic acidosis is not merely extracellular but intracellular, reshaping metabolism through direct biochemical mechanisms. Acidic pH and elevated lactate jointly suppress glycolysis by inhibiting HK, PFK1 and GAPDH, enforcing a low-flux, energy-efficient state. Meanwhile, pyruvate enters the TCA cycle through a pyruvate - lactate -export - reimport - lactate - pyruvate cycle that both fuels mitochondrial metabolism and maintains lactic acidosis intracellularly and extracellularly. Lactic acidosis also reprograms anaplerosis by promoting lactate-derived oxaloacetate formation and reducing glutamine dependence. Together, these findings establish lactic acidosis as an active regulator of cancer metabolism, revealing a distinct metabolic state. This coupled lactate-proton state drives coordinated metabolic reprogramming across glycolysis and mitochondrial metabolism. representing a fundamental tumor adaptation that may be exploited to disrupt cancer metabolic resilience.

Keywords:  TCA cycle; Warburg effect; glycolysis; lactic acidosis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.jbc.2026.113150
Pharm Biol. 2026 Dec;64(1): 725-748

Wubie Fanchun Formula-inducible metabolites in primary ovarian insufficiency model mice that facilitate ovarian renovation.

Yun Chen, Shanshan Chen, Bingbing Song, Xinfang Xia, Kaiqing Zhang, Li Chen, Lei Chi, Qiong Wang.

   CONTEXT: Premature ovarian insufficiency (POI), defined as ovarian activity cessation before age 40, significantly impacts both fertility and long-term health, with currently inadequate treatment options available. Wubie Fanchun Formula (WBFC) has been clinically used for over 20 years, showing benefits in TCM symptoms and hormone levels in POI patients with liver-kidney deficiency. However, its active components and mechanistic basis are still largely unknown.
OBJECTIVE: To characterize the active ingredients and delineate the pharmacological basis of WBFC's action in managing POI.
MATERIALS AND METHODS: LC-TOF-MS was used to identify WBFC's chemical constituents. Network pharmacology analysis pinpointed candidate mechanisms, which were tested in a 4-VCD-induced POI mouse model. Metabolic dysfunction was characterized via pyruvate tolerance tests, liver glycogen staining, and untargeted metabolomics. Key metabolites regulated by WBFC in model mice, phosphatidylinositol 38:5 (PI) and glutamine (GLN), were supplemented to validate their roles in POI pathology.
RESULTS: 25 bioactive constituents in WBFC were found by LC-TOF-MS analysis. WBFC ameliorated ovarian dysfunction and activated the PI3K/AKT/FOXO3a pathway in parallel with simultaneously improving systemic metabolic parameters. Metabolomics identified PI and GLN among the top 30 most significantly altered metabolites, both showing marked depletion in POI mice and substantial restoration following WBFC treatment. Functional validation through exogenous supplementation demonstrated that combined PI and GLN administration effectively rescued ovarian dysfunction and specifically reactivated the ovarian PI3K-AKT pathway in 4-VCD induced POI mice.
DISCUSSION AND CONCLUSION: Amino acids, saponins, anthraquinones, and carbohydrates are the main chemical components of WBFC. WBFC ameliorated POI and activated PI3K/AKT/FOXO3a signaling through metabolic regulation, with PI and GLN identified as critical therapeutic mediators.

Keywords:  PI3K/AKT/FOXO3a pathway; Primary ovarian insufficiency; Wubie Fanchun Formula; glutamine; phosphoinositol 38:5

DOI:  https://doi.org/10.1080/13880209.2026.2668132
Molecules. 2026 Apr 23. pii: 1394. [Epub ahead of print]31(9):

Plant-Derived Modulators of Tumor Metabolism as Novel, Efficacious, and Low-Toxicity Therapeutic Agents for Cancer Treatment.

Tania Mmapule Maphoso, Dakalo Portia Ramali, Thanyani Mulaudzi, Vinesh Maharaj, Cathryn Helena Stanford Driver, Botle Precious Damane.

  Metabolic reprogramming is a core hallmark of malignancy, enabling tumor cells to sustain rapid proliferation, evade immune elimination, and develop resistance to therapy. Although a wide range of plant-derived phytochemicals exhibit anticancer activity with comparatively low toxicity, their capacity to disrupt specific metabolic dependencies exploited by tumors has not been comprehensively synthesized. This review brings together current mechanistic evidence showing how major phytochemical classes, including polyphenols, terpenes and terpenoids, glucosinolates, and alkaloids, interfere with pathways central to tumor metabolic fitness, such as aerobic glycolysis, pentose phosphate pathway flux, mitochondrial substrate oxidation, glutamine dependence, and redox homeostasis. It further introduces a pathway-focused framework that links phytochemical mechanisms to quantifiable metabolic outcomes and highlights their potential to remodel the tumor microenvironment by altering nutrient competition, oxidative stress responses, and hypoxia-driven signaling. Key barriers such as poor systemic bioavailability, rapid metabolic degradation, and limited tissue penetration are assessed alongside emerging formulation and delivery strategies designed to enhance therapeutic exposure while preserving low-toxicity profiles. Mapping these mechanistic insights onto clinical development needs allows prioritization of specific phytochemical-metabolic pathway pairs with the strongest potential for translation. This positions plant-derived metabolic disruptors as promising candidates for next-generation, low-toxicity anticancer therapies that strategically exploit defined metabolic vulnerabilities.

Keywords:  cancer metabolism; metabolic modulators; metabolic reprogramming; phytochemicals; tumor microenvironment

DOI:  https://doi.org/10.3390/molecules31091394
Nat Aging. 2026 May 14.

Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.

David E Lee, Lauren K McKay, Akshay Bareja, JiaCheng Yang, Wentao He, Demitrius A Hill, James R Bain, Shihuan Kuang, Guo-Fang Zhang, Christopher B Newgard, James P White.

Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.

DOI: https://doi.org/10.1038/s43587-026-01120-3
Cancer Metab. 2026 May 12. pii: 12. [Epub ahead of print]14(1):

Normoxic HIFα-mediated metabolic rewiring in cancer as a novel therapeutic target of tumor heterogeneity.

Anaís Sánchez-Castillo, Jairo G E Lommen, Denise Consten, Kim Savelkouls, Lydie M O Barbeau, Kasper M A Rouschop, Marc A Vooijs, Kim R Kampen.

   BACKGROUND: Hypoxia-inducible factors (HIF1α, HIF2α) influence radiotherapy responses in non-small cell lung cancer (NSCLC) and glioblastoma (GBM), tumors characterized by oxygen and HIF expression heterogeneity. As the function of HIFs in normoxic metabolic function remained unexplored, we investigated how loss of HIF1α or HIF2α affects metabolism, redox homeostasis, and radiotherapy sensitivity in normoxia, aiming to identify opportunities for combined metabolic inhibition.
METHODS: NSCLC HIF1α or HIF2α knockout (KO) and HIFα wildtype (WT) models were analyzed using 13C-glucose mass spectrometry tracing before and after radiotherapy treatment. Metabolic phenotypes were validated using serine/glycine (ser/gly) synthesis enzyme expression by immunoblot and quantitative PCR, redox by ROS flow cytometry analysis, and DNA methylation by 5mC dot-blot assessment. Pharmacological inhibition of ser/gly metabolism was performed in both NSCLC and GBM models using the repurposed serine-glycine conversion inhibitor sertraline using incucyte confluency monitoring.
RESULTS: Both HIF1α and HIF2α KO cells displayed reduced glycolysis and compensatory ser/gly pathway hyperactivation. HIF1α KO cells channeled ser/gly into nucleotide (particularly TTP) synthesis and glutathione (GSH)-mediated antioxidant defense, conferring radiotherapy resistance. In contrast, HIF2α KO cells preferentially used serine for α-ketoglutarate (α-KG) production, the enhanced NADH/methionine-dependent redox system and the methionine cycle to support enhanced DNA methylation. Subsequently, following irradiation, only the radiation resistant HIF1α KO cells further enhanced ser/gly metabolism, increasing AMP/ATP and GSH/GSSG (oxidized GSH) ratios, whereas HIF2α KO cells failed to adapt and accumulated oxidative stress. HIF1α KO cells were more sensitive to pharmacological inhibition of ser/gly metabolism by sertraline, particularly in combination with irradiation, which abrogated their radioresistant phenotype in both NSCLC and GBM models.
CONCLUSIONS: HIF1α-deficient cells rely on ser/gly synthesis for nucleotide production and antioxidant defense, promoting radiotherapy resistance while creating vulnerability to sertraline plus irradiation. HIF2α-deficient cells favor α-KG production and methionine-driven alternative redox and methylation pathways. Targeting ser/gly synthesis may overcome HIF-gradient-dependent radiotherapy resistance.

Keywords:  Cancer metabolism; Hypoxia inducible factors; Tumor heterogeneity

DOI:  https://doi.org/10.1186/s40170-026-00433-6
Mol Ther. 2026 May 13. pii: S1525-0016(26)00395-3. [Epub ahead of print]

Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice.

Jiaming Wang, Coleman T Turgeon, Perry R Loken, Heather Gray-Edwards, Guangping Gao, Silvia Tortorelli, Dan Wang, Kevin A Strauss.

Branched-chain 2-ketoacid dehydrogenase (BCKDH) deficiency (maple syrup urine disease; MSUD) causes lethal encephalopathy by disrupting cerebral metabolism, a process imperfectly reflected by circulating biomarkers. Diet and liver transplantation stabilize peripheral metabolites but fail to restore brain neurochemistry, demarcating the central nervous system as the decisive therapeutic compartment. To define the pathogenesis of intoxication and its therapeutic response, we performed paired serum-brain metabolomics in Bckdha-/- mice treated with a systemic AAV9 dual-gene vector encoding human BCKDHA and BCKDHB (A-BiP-B). Untreated neonates exhibited a ninefold elevation of brain 2-ketoisocaproate (2KIC) accompanied by cerebral depletion of glutamate and glutamine, as well as shifts in tricarboxylic acid cycle and ketone body metabolism. These disturbances originated from reversal of branched-chain aminotransferase (BCAT2) flux and destabilization of glutamate-2KG mass balance, producing divergent metabolic endophenotypes in blood versus brain. A single intravenous injection of A-BiP-B rescued mice from fatal encephalopathy, partially restored cerebral BCKDHA mRNA expression, and brought core brain neurochemical endpoints within wild-type range despite persistent elevation of serum 2-ketoacids. These findings expose limitations of current MSUD management and establish systemic dual-gene therapy as a means of restoring neurochemical homeostasis while enabling survival on unrestricted protein intake.

DOI: https://doi.org/10.1016/j.ymthe.2026.05.008
NMR Biomed. 2025 Dec;38(12): e70167

Nuclear Magnetic Resonance-Based Metabolomic Profiling in Fibromyalgia Patients.

Hatice Kübra Aşık, Yıldız Atamer, Metin Demirel, Tuğba Şahbaz, Sahabettin Selek, Mehtap Alim, Aytaç Atamer.

  Fibromyalgia (FM) is a multifactorial syndrome with poorly understood pathophysiology, characterized by chronic widespread pain and fatigue affecting the central and peripheral nervous systems, as well as the endocrine and muscular systems. These characteristics create significant challenges in diagnosis and treatment. This study compared the metabolic profiles of FM patients and healthy controls using one-dimensional (1D) 1H nuclear magnetic resonance (NMR) spectroscopy and multivariate statistical analysis to identify potential biomarkers associated with FM symptoms. Urine and serum samples from 50 FM patients and 50 healthy individuals underwent untargeted metabolic profiling. Quantitative 1H-NMR spectroscopy was used to determine metabolic changes. Chemometric models and receiver operating characteristic (ROC) curves were generated using the MetaboAnalyst platform. Fold change (FC) analysis and t-tests were conducted to determine statistically significant differences between groups. Our findings showed significant differences at the metabolic level between FM patients and healthy controls. Increased urea, glutamate, valine, taurine, proline, glycine, and homoserine metabolites, and decreased benzoate, leucine, π-methylhistidine, galactitol, τ-methylhistidine, glutamine, 3-hydroxykynurenine, and fructose levels were observed in FM serum; while increased malate, dimethylamine, trimethylamine N-oxide (TMAO), creatine phosphate, N-phenylacetylglycine, N-acetylglutamate (NAG), hippurate, and urea levels were observed in FM urine, and decreased guanidoacetate, creatine, malonate, serine, glucuronate, creatinine, and uracil levels were observed. Serum glutamate was positively correlated with waist/hip ratio (WHR) and negatively correlated with Fibromyalgia Impact Questionnaire (FIQ) and Visual Analog Scale (VAS); negative correlations existed between taurine and FIQ and VAS; a positive correlation existed between urea and WHR; there was a positive correlation between anserine and body mass index (BMI). Also, in urine, there were positive correlations between TMAO, N-phenylacetylglycine, glutamate, and xylose and WHR; negative correlations existed between glutamine and FIQ; and a positive correlation existed between glucuronate and FIQ. Our findings provide important information about potential biomarkers, associated different metabolites, and metabolic pathways of FM patients; we think that they will provide new insight into the pathogenesis of the disease and help expand our knowledge.

Keywords:  metabolomics; primer fibromyalgia syndrome; proton nuclear magnetic resonance (1H–NMR) spectroscopy

DOI:  https://doi.org/10.1002/nbm.70167
Cancers (Basel). 2026 May 03. pii: 1474. [Epub ahead of print]18(9):

Amino Acid-Driven Mitochondrial Metabolic Rewiring Controls Antitumor Immunity.

Suji Ham, Min-Jeong Jo, Kwon-Ho Song, Bo-Hyun Choi.

  Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino acid metabolism within mitochondria contributes to tumor progression and influences immune cell fate and effector function. These effects are mediated through biosynthetic precursor generation for lipid, nucleotide, and polyamine synthesis, maintenance redox homeostasis through glutathione and NAD+ metabolism, and regulation of gene expression through aryl hydrocarbon receptor signaling. In this review, we discuss four major mitochondrial amino acid metabolic pathways: glutamine-driven anaplerosis, serine/glycine-dependent one-carbon metabolism, arginine-ornithine metabolism, and tryptophan-kynurenine metabolism. We examine how these pathways are rewired in cancer cells, how they influence immune cell function through direct or mitochondria-associated mechanisms, and how such metabolic reprogramming promotes tumor progression while impairing antitumor immunity. Finally, we consider therapeutic strategies to improve cancer immunotherapy by targeting amino acid metabolism, including mitochondrial metabolic enzymes. This review may help guide the development of more effective metabolic biomarkers and mitochondria-based therapeutic strategies for cancer immunotherapy.

Keywords:  amino acid metabolism; antitumor immunity; immunotherapy resistance; mitochondrial metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18091474
Lab Anim (NY). 2026 May 12.

Sex-specific systemic and brain metabolic responses to a standardized ketogenic diet in mice.

Charlotte Lorin, Giacomo Diaceri, Miguel Garcia, Emmanuelle Logette, Henry Markram, Daniel Keller.

Ketogenic diets (KDs) are widely used in preclinical research to investigate metabolism and neurological function, yet many studies lack methodological consistency and frequently exclude female animals. Here we investigated sex-specific systemic and brain metabolic responses to a standardized KD in mice, highlighting the need to include both sexes. Using the widely used C57BL/6J mouse strain and the Bio-Serv KD, systemic and brain cell metabolism were examined in both sexes. Significant sex-based metabolic differences, probably influenced by hormones, were observed: females were leaner, exhibited higher interindividual variability in weight loss, higher baseline ketone (β-hydroxybutyrate) levels and a faster but less pronounced drop in glycemia compared with males. By contrast, cerebral metabolism appeared stable across sexes, with no significant differences detected in isolated brain cells, suggesting that sex-specific systemic adaptations are counterbalanced at the brain level to maintain functional stability. Regarding brain cell analysis, a lactate gradient from astrocytes to neurons was observed, reflecting preferential astrocytic lactate production and neuronal utilization, along with distinct glucose and glutamine distributions. Overall, our findings validate an animal model of sustained, stable ketosis and emphasize the importance of including both sexes in KD research, providing a foundation for studying sex-specific metabolic adaptations and informing potential personalized dietary strategies.

DOI: https://doi.org/10.1038/s41684-026-01732-7
Curr Med Sci. 2026 May 13.

Sijunzi Decoction Reverses Metabolic Adaptation and Induces Ferroptosis in Cisplatin-Resistant Non-small Cell Lung Cancer: An Integrative Metabolomics-Pharmacology Analysis.

Wen-Jun Liu, Han-Yu Dong, Chun-Ying Liu, Chun Wang.

   OBJECTIVE: To investigate the mechanistic role of Sijunzi decoction (SJZD) in overcoming chemoresistance through the suppression of adaptive metabolic responses in non-small cell lung cancer (NSCLC).
METHODS: Chemical profiling of SJZD-derived components in systemic circulation was conducted using liquid chromatography-tandem mass spectrometry (LC‒MS/MS) in Sprague-Dawley rats. Multiomics integration and network pharmacology were employed to identify convergent targets shared by the bioactive constituents of SJZD and genes associated with cisplatin resistance. In vitro functional assessments using cisplatin-resistant human lung adenocarcinoma (A549/DDP) cells included the following: quantification of cell viability via Cell Counting Kit-8 (CCK-8) assays; evaluation of mitochondrial bioenergetics through targeted metabolomic profiling; and ultrastructural characterization of ferroptotic morphology via transmission electron microscopy (TEM). Cellular redox homeostasis was dynamically monitored using fluorescent probes, including a DCFH-DA probe for reactive oxygen species (ROS) and a C11-BODIPY581/591 probe for lipid peroxidation. siRNA-mediated gene silencing and immunohistochemical analysis were performed to elucidate the functional hierarchy of the p62/Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant axis. Complementary in vivo validation was performed using BALB/c nude mice bearing A549/DDP xenografts, with longitudinal monitoring of tumor progression under SJZD treatment regimens.
RESULTS: Untargeted metabolomics of SJZD-medicated serum revealed 392 differentially abundant metabolites, with pathway enrichment revealing significant dysregulation of glutamine metabolism. Structural validation confirmed 55 bioactive components of SJZD in serum, including glycyrrhizin, ginsenoside Ro, liquiritigenin, and atractylenolide I. Integration of these components with disease targets yielded 355 overlapping genes associated with both SJZD activity and cisplatin-resistant NSCLC, with significant enrichment in oxidative stress response pathways. Experimental assays confirmed that SJZD induced ferroptosis in cisplatin-resistant A549/DDP cells, as evidenced by disrupted iron homeostasis, lipid peroxidation, and characteristic mitochondrial damage. These effects and subsequent cell death were specifically abrogated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) but not by apoptosis inhibition, confirming that ferroptosis is the primary mechanism of cell death. Mechanistically, the inhibition of p62/Keap1/Nrf2 signaling was involved in the modulation of SJZD-induced ferroptosis both in vitro and in vivo.
CONCLUSIONS: SJZD counteracts metabolic adaptation through ferroptosis mediated by the inhibition of p62/Keap1/Nrf2 in cisplatin-resistant NSCLC.

Keywords:  Adaptive response; Cisplatin resistance; Ferroptosis; Metabolic reprogramming; Non-small cell lung cancer; Sijunzi decoction

DOI:  https://doi.org/10.1007/s11596-026-00203-x
Clin Sci (Lond). 2026 May 14. pii: CS20250414. [Epub ahead of print]

The metabolic effects of post-sepsis feeding of meals with only essential amino acids.

Nicolaas E P Deutz, Gabriella Am Ten Have, Sarah A Rice, Marina B W Horner, Ilaria Minussi, Mariëlle Pkj Engelen.

  Nutritional support is a vital component of the rehabilitation process following sepsis. Essential amino acids (EAA) are recognized as a critical component for stimulating anabolism. However, it remains unclear whether EAA supplementation alone is more effective than providing a complete profile of all amino acids (TAA). We studied amino acid metabolism in 51 catheterized pigs (±27kg) using the pulse tracer approach over a 7-day recovery period following sepsis. Animals were randomly and blindly assigned to receive post-sepsis nutrition containing either an EAA or a TAA mixture based on the composition of pig muscle. Statistical analyses were performed using a generalized linear mixed model. Plasma concentrations of EAA increased substantially in the EAA group post-sepsis (interaction effect, p<0.001), while those of non-essential amino acids increased in both groups (time effect, p<0.001). Whole body intracellular production of most AA was reduced on day 3 and remained low on day 7 post-sepsis, with only small differences observed between the two groups. On day 7 post-sepsis, pigs receiving only EAA showed significantly (all p<0.001) lower intracellular production of hydroxyproline (-36%), ornithine (-11%), and tryptophan (-20%) and higher production of arginine (66%), citrulline (18%), glutamine (18%), taurine (22%) and some EAA. The EAA group showed a significantly higher net protein breakdown post-sepsis. In this sepsis-recovery pig model, dietary supplementation of both EAA and TAA failed to normalize the intracellular production of amino acids. More importantly, providing only EAA resulted in a significantly greater net protein breakdown compared to the TAA group.

Keywords:  amino acids; metabolism; nutrition; sepsis

DOI:  https://doi.org/10.1042/CS20250414
Acta Neuropathol Commun. 2026 May 13.

Glioblastoma cells utilize evolutionarily adapted cell metabolism to promote their malignant proliferation.

Maxim M Bespalov, Vasiliki Gkini, Zeynep Iloglu, Seiya Yamada, Akira Nemoto, Pauliina Filppu, Kalevi Trontti, Liliia Andriichuk, Olli Pietiläinen, Vadim Le Joncour, Anni I Nieminen, Pirjo Laakkonen, Takashi Namba.

  Glioblastoma is the most aggressive primary brain tumor in adults, with limited therapeutic success and, therefore, poor prognosis. Its malignancy is partly driven by the high proliferative capacity of glioblastoma cells, yet the underlying molecular mechanisms remain unclear. Recent studies have revealed transcriptomic similarities between glioblastoma cells and human fetal neural stem/progenitor cells (NSCs), suggesting that glioblastoma may exploit developmental programs that promote NSC proliferation. Fetal human NSCs rely on glutaminolysis-a metabolic pathway induced by the human-specific mitochondrial protein ARHGAP11B-to sustain proliferation. Here, we show that ARHGAP11B expression correlates with glioma malignancy and is essential for glioblastoma cell proliferation, implicating a critical role of glutaminolysis in tumor growth. Among glutaminolysis-related enzymes, glutamic-oxaloacetic transaminase 2 (GOT2) shows a strong positive correlation with glioma grade and poor patient prognosis. Functional assays reveal that GOT2 knockdown significantly suppresses glioblastoma cell growth, indicating that GOT2-mediated glutaminolysis is critical for their proliferation. Metabolomic profiling further shows that GOT2 is required for nucleotide precursor synthesis, underscoring its role in supporting DNA replication. Consistently, GOT2 depletion reduces the proportion of glioblastoma cells in the S phase of the cell cycle. These findings suggest glioblastoma cells hijack an evolutionarily adapted metabolic program to support malignant growth.

Keywords:  ARHGAP11B; Cell proliferation; GOT2; Glioblastoma; Glutamic-oxaloacetic transaminase; Glutaminolysis; Metabolic reprogramming; Mitochondrial metabolism; Nucleotide biosynthesis; Oncometabolism

DOI:  https://doi.org/10.1186/s40478-026-02318-7
Biochim Biophys Acta Rev Cancer. 2026 May 08. pii: S0304-419X(26)00077-6. [Epub ahead of print]1881(4): 189605

Reprogramming regulatory T cell plasticity for cancer immunotherapy.

Mark E Issa, Alejandro Schcolnik-Cabrera, Rosanna Monetta.

  Regulatory T cells (Tregs) maintain immune homeostasis by suppressing excessive immune responses. In the context of cancer, Tregs are abundantly recruited to inhibit immunity against tumoral cells, facilitate immune evasion, and promote tumor progression. While Treg depletion strategies have repeatedly failed in the clinic due to severe autoimmune side effects, lack of specificity, and rapid compensatory recruitment, a critical unmet need remains for safer and more effective approaches. Emerging evidence highlights the remarkable plasticity of Tregs, allowing them to adopt an inflammatory phenotype in response to tumor-associated cytokines. Thus, leveraging this plasticity, rather than attempting broad depletion, may represent a superior anticancer strategy. This plasticity is marked by the expression of transcription factors like T-bet (Th1-like) and RORγt (Th17-like), the production of pro-inflammatory cytokines such as IFN-γ and IL-17, and even the acquisition of differential energetic preferences pertaining to glucose or glutamine. These changes can weaken Treg suppressive functions or paradoxically enhance inflammation in the tumor microenvironment, thereby creating a complex interplay between immune suppression and anti-tumor effector activity. Understanding the molecular cues driving Treg plasticity is therefore critical for designing novel therapies that shift Tregs toward an effector-like state, ultimately enhancing anti-tumor immunity and improving the efficacy of current immunotherapies. This review offers a fresh perspective on how Treg plasticity can be therapeutically harnessed to overcome the persistent limitations of conventional Treg-targeted approaches.

Keywords:  Antitumor immunity; Immune infiltration; Immune phenotypes; Treg cells; Treg plasticity

DOI:  https://doi.org/10.1016/j.bbcan.2026.189605
Int J Mol Sci. 2026 Apr 29. pii: 3984. [Epub ahead of print]27(9):

Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.

Qingru Wu, Jing Tian, Yan Gu, Xiaoying Bi, Hailing Zhang.

  Depression is a highly heterogeneous psychiatric disorder with its pathogenesis increasingly linked to dysregulated neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), play a pivotal role in the initiation and progression of the neuroinflammation and the pathophysiology of depression. These cells exhibit a dual role in pro- and anti-inflammatory processes, dynamically regulating immune responses through immunometabolic reprogramming in response to environmental cues. This review elaborates how metabolic remodeling in microglia, particularly within glucose, lipid, and amino acid pathways, drives their polarization toward a pro-inflammatory phenotype. This shift promotes depression pathogenesis via the release of inflammatory factors, disruption of synaptic plasticity, and mediation of neurotoxicity. We further discuss the impact of existing antidepressants on cellular metabolism and highlight the promise and challenges of targeting specific microglial metabolic pathways as a novel therapeutic strategy. This synthesis provides new insights into the immunometabolic mechanisms of depression and outlines directions for developing targeted treatments.

Keywords:  depression; glutamate; glycolysis; immunometabolism; lipid metabolism; metabolic reprogramming; microglia; mitochondria; neuroinflammation

DOI:  https://doi.org/10.3390/ijms27093984
Trends Cancer. 2026 May 14. pii: S2405-8033(26)00083-X. [Epub ahead of print]

Amino acid metabolism at the senescence-cancer interface.

Giulia Lori, Caterina Mancini, Erica Pranzini, Francesca Magherini, Maria L Taddei.

  Amino acid (AA) metabolism plays a fundamental role in the regulation of cellular senescence. Through profound AA metabolic reprogramming, senescent stromal cells can sustain tumor progression, metastatic dissemination, and the establishment of an immunoevasive microenvironment. Conversely, alterations in AA availability within the tumor microenvironment can enforce tumor-suppressive senescence in malignant cells. In this review, we discuss how senescence-driven rewiring of AA metabolism shapes tumor-stroma interactions and immune responses. We propose that AA-targeted interventions may represent an effective therapeutic strategy to simultaneously mitigate the detrimental effects of stromal senescence while inducing tumor-suppressive senescence in cancer cells.

Keywords:  amino acid metabolism; cellular senescence; immunoevasion; metastatic colonization; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2026.04.007