bims-glucam 2025-12-21 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–12–21
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Splicing factor SF3B4 promotes mitochondrial glutamine metabolism in hepatocellular carcinoma by regulating GLS1 isoform switching.
Could Glutamine Feed Epileptogenesis?
Celastrol delays the progression of hepatocellular carcinoma by suppressing SLC1A5-mediated glutamine dependence.
The role of glutamine/Nrf2-enhanced PHGDH in Cadmium-induced lactate utilization.
Exploring the role of GLS1 in colorectal cancer progression through the glutamine metabolism-PI3K signaling-autophagy axis.
Erianin inhibits endometrial cancer cell proliferation and migration by modulating glutamine metabolism through the ERK signaling pathway.
HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction.
The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells.
Bcl-2 protein Noxa is required for metabolic reprogramming to glutamine dependence and for apoptosis in stimulated human CD8 + T cells.
L-Theanine Uptake via Solute Carrier Family 38 Member 1 Inhibits Neuroblastoma Cell Growth.
Liver cancer chronically exposed to palmitate acquires ferroptosis resistance via the downregulation of glutamine-driven hepcidin expression.
Ammonia reduces glutamine synthetase expression in astrocytes via activation of Hippo-YAP signaling pathways.
Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors.
Identification of the function of the metabolite repair enzyme Nit1: the story of a collaboration with Arthur Cooper.
Multi-omics analysis reveals metabolic diversity underlying endothelial cell functions.

Biochem Biophys Res Commun. 2025 Dec 15. pii: S0006-291X(25)01850-9. [Epub ahead of print]796 153134

Splicing factor SF3B4 promotes mitochondrial glutamine metabolism in hepatocellular carcinoma by regulating GLS1 isoform switching.

Seungyeon Yang, Minbeom Ko, Wei Zhang, Seung Min Jeong.

  Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to nutrient stress and sustain uncontrolled proliferation. In hepatocellular carcinoma (HCC), glutamine metabolism is markedly upregulated and plays a pivotal role in supporting tumor growth and survival. However, the molecular mechanisms underlying this metabolic shift remain poorly understood. Here, we identify the splicing factor SF3B4 as a key regulator of glutamine metabolism in HCC through its control of glutaminase 1 (GLS1) alternative splicing. SF3B4 is highly expressed HCC and is essential for tumor cell proliferation, migration and colony formation. Mechanistically, SF3B4 preferentially promotes the production of the GAC isoform of GLS1, which exhibits higher catalytic activity, while repressing the KGA isoform. Genetic or pharmacological inhibition of SF3B4 leads to reduced GAC expression, decreased GLS enzymatic activity, impaired glutaminolysis, and suppression of glutamine-driven mitochondrial respiration. Moreover, SF3B4 is required for tumor cell survival under glucose-deprived conditions, highlighting its role in supporting metabolic flexibility under nutrient stress. Collectively, these findings uncover a previously unrecognized function of SF3B4 in promoting mitochondrial glutamine metabolism in HCC and suggest that the SF3B4-GAC axis may represent a potential therapeutic target for glutamine-addicted liver cancers.

Keywords:  GLS1; Glutamine metabolism; HCC; SF3B4

DOI:  https://doi.org/10.1016/j.bbrc.2025.153134
Epilepsy Curr. 2025 Dec 09. 15357597251399047

Could Glutamine Feed Epileptogenesis?

Karin Borges.

DOI: https://doi.org/10.1177/15357597251399047
Toxicol Appl Pharmacol. 2025 Dec 14. pii: S0041-008X(25)00466-1. [Epub ahead of print]507 117690

Celastrol delays the progression of hepatocellular carcinoma by suppressing SLC1A5-mediated glutamine dependence.

Simeng Xiao, Yun Zhao, Zhiguo Chen, Yangkun Xiong, Dingmei Zhang, Gang Zhou, Cong Zhang.

  Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the Tripterygium wilfordii Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells in vitro and in vivo. Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.

Keywords:  Celastrol; GLS1; Glutamine metabolism; Hepatocellular carcinoma; SLC1A5

DOI:  https://doi.org/10.1016/j.taap.2025.117690
Free Radic Biol Med. 2025 Dec 14. pii: S0891-5849(25)01431-5. [Epub ahead of print]244 296-311

The role of glutamine/Nrf2-enhanced PHGDH in Cadmium-induced lactate utilization.

Yuxin Pang, Shengnan Li, Qingxuan Zhang, Yuting Liu, Ying Kong, Jun Cao.

  Cadmium (Cd) is a toxic heavy metal that is closely associated with the occurrence and progression of lung cancer. Our previous studies showed that Cd promoted lactate utilization and the expression of phosphoglycerate dehydrogenase (PHGDH), which is the key enzyme in serine biosynthesis. In this study, the role of PHGDH in Cd-induced lactate utilization was investigated. First, we found that PHGDH enhanced Monocarboxylate transporter 1 (MCT1) but not MCT4 in both A549 cells and tumor tissues formed by injection of siPHGDH-treated A549 cells in male BALB/c mice. Then, glutamine deprivation and transfection with siASCT2 (Alanine-Serine-Cysteine Transporter 2) revealed that glutamine was involved in Cd-induced Nrf2, PHGDH, glycolysis-related proteins, MCT1 and cell migration. Moreover, inhibition of Nrf2 with ML385 attenuated Cd-induced glutamine metabolism, PHGDH, MCT1, lactate production, and cell migration, while activation of Nrf2 with RTA-408 had the opposite effect. In addition, using RTA-408, ML385, glutamine addition and deprivation, we discovered that glutamine metabolism and Nrf2 interacted to enhance PHGDH and PHGDH-induced lactate utilization. Collectively, these findings suggest that PHGDH plays a crucial role in Cd-induced lactate utilization, and the mechanism underlies the interaction between glutamine and Nrf2. This study provides insights into the mechanism of Cd-related tumorigenesis and toxicity.

Keywords:  Cadmium; Glutamine; Lactate utilization; Nrf2; PHGDH

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.015
Int J Surg. 2025 Dec 16.

Exploring the role of GLS1 in colorectal cancer progression through the glutamine metabolism-PI3K signaling-autophagy axis.

Yang Xie, Lu Han, Yiyi Jin, Jun Li, Qing Tao, Yonghui Wu, Zide Liu, Chaotao Tang, Xingxing He, Youxiang Chen, Chunyan Zeng.

   BACKGROUND: Glutamine and glutamate metabolism play crucial roles in the development of various tumors, yet their specific involvement in colorectal cancer (CRC) remains poorly understood.
PURPOSE: This study aimed investigate the roles of glutamine and glutamate metabolism in CRC progression and to elucidate themolecular mechanisms by which their key regulatory enzyme, GLS1, contributes to CRC development.
METHODS: Blood samples from healthy controls and individuals with colorectal polyp (CRP), colorectal adenoma (CRA), early-stage CRC (ECRC), and advanced CRC (ACRC) were analyzed using liquid chromatography‒mass spectrometry and gas chromatography‒mass spectrometry to quantify metabolite levels. Bioinformatic analyses and molecular experiments were performed to examine GLS1 expression and function in CRC. GLS1 expression was manipulated using siRNAs and lentiviral vectors for knockdown and overexpression, respectively. Functional assays, including CCK-8, Transwell, and colony formation assays, were used to assess the effects of GLS1 on CRC cell proliferation, migration, and invasion. Rescue experiments with rapamycin (autophagy activator) and LY294002 (PI3K inhibitor) were conducted to explore underlying mechanisms. An in vivo tumorigenesis model in nude mice was also established.
RESULTS: Patients with ACRC exhibited significantly reduced circulating glutamine levels compared with healthy controls, whereas glutamate levels were elevated across all disease stages (CRP, CRA, ECRC, and ACRC). Circulating glutamine was associated with both CRC diagnosis and prognosis. GLS1 was upregulated in CRC tissues and cell lines and correlated with poor clinical outcomes. Glutamine deprivation and GLS1 knockdown suppressed CRC cell proliferation, migration, and invasion, while GLS1 overexpression enhanced these malignant phenotypes. Bioinformatic analysis revealed that GLS1 activates the PI3K signaling pathway in CRC, which was confirmed by Western blotting following GLS1 knockdown and overexpression. Additionally, glutamine deprivation and GLS1 knockdown induced autophagy in CRC cells, whereas GLS1 overexpression inhibited autophagy, as further evidenced by transmission electron microscopy. Rescue experiments demonstrated that LY294002 and rapamycin reversed the effects of GLS1 on CRC cell proliferation, migration, and invasion . In vivo, GLS1 overexpression promoted tumor growth in nude mice, which was attenuated by LY294002 and rapamycin treatment.
CONCLUSION: Glutamine and glutamate show promise as diagnostic and prognostic biomarkers for CRC. GLS1 plays a critical role in CRC progression by activating the PI3K-AKT signaling pathway and modulating autophagy. These findings provide new insights into glutamine metabolism in CRC and highlight GLS1 as a potential therapeutic target.

Keywords:  GLS1; PI3K-AKT; autophagy; colorectal cancer; glutamine

DOI:  https://doi.org/10.1097/JS9.0000000000004406
Am J Transl Res. 2025 ;17(11): 8964-8972

Erianin inhibits endometrial cancer cell proliferation and migration by modulating glutamine metabolism through the ERK signaling pathway.

Qing Huang, Yangfeng Xu, Huiping Li, Ting Zhang.

   OBJECTIVE: To investigate the therapeutic use of erianin, a bioactive compound derived from traditional Chinese medicine, in the treatment of EC and its regulatory effects on glutamine metabolism.
METHODS: Human Endometrial cancer (EC) cell lines, HEC-1A and Ishikawa, were exposed to erianin, and cellular proliferation and migratory capacity were assessed using the Cell Counting Kit-8 (CCK-8) assay and the Transwell migration assay, respectively. Glutamine metabolism was evaluated by quantifying intracellular glutamine, α-ketoglutaric acid (α-KG), and adenosine triphosphate (ATP). A xenograft tumor model was used to validate the antitumor efficacy of erianin in vivo. The changes in extracellular signal-regulated kinase (ERK) signaling were analyzed by western blotting.
RESULTS: Erianin treatment significantly inhibited the proliferation and migration of EC cells in vitro and suppressed tumor growth in vivo. Additionally, erianin downregulated glutamine metabolism, as evidenced by reduced levels of glutamic acid, α-KG, and ATP. Interestingly, activation of the ERK signaling pathway mitigated the antitumor and metabolic inhibitory effects of erianin on EC cells.
CONCLUSION: Erianin inhibits glutamine metabolism and suppresses the growth of EC through the ERK signaling pathway.

Keywords:  ERK; Endometrial cancer; glutamine metabolism; migration

DOI:  https://doi.org/10.62347/KENY2426
Cancer Lett. 2025 Dec 12. pii: S0304-3835(25)00791-8. [Epub ahead of print]639 218219

HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction.

Fei Wu, Jiannan Shen, Zhiting Zhao, Yan Chen, Binhui Ren, Ming Li, Rong Yin, Yanyan Zhang, Shaorong Yu.

  Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and EGFR-mutant tumors show limited response to current immunotherapy. The immunosuppressive tumor microenvironment, particularly metabolic constraints on effector T cells, is increasingly recognized as a major barrier to effective anti-tumor responses. HHLA2, a B7 family member frequently elevated in EGFR-mutant NSCLC, has an incompletely defined role in immune escape. In this study, we demonstrate that tumor-derived HHLA2 engages the inhibitory receptor KIR3DL3 on CD8+ T cells, driving T cell exhaustion through metabolic reprogramming of amino acid utilization. HHLA2-KIR3DL3 signaling suppresses glutamine utilization through ERK/MAPK-dependent repression of SLC1A5, SLC38A2, and ADHFE1, key glutamine transporters and metabolic enzymes, thereby inducing metabolic insufficiency and dysfunctional cytokine production in CD8+ T cells, including reduced IFN-γ, TNF-α, and increased IL-10. Disruption of this axis-via HHLA2 deletion or antibody blockade-restored T cell metabolism and effector function, leading to attenuated tumor progression in humanized mouse models. Notably, HHLA2/KIR3DL3 inhibition synergized with EGFR tyrosine kinase inhibitors to enhance anti-tumor immunity and suppress tumor progression. Together, these findings identify HHLA2-KIR3DL3 as a key immunosuppressive pathway in EGFR-mutant NSCLC and may provide a rationale for therapeutic targeting to improve clinical outcomes.

Keywords:  CD8(+) T cell exhaustion; EGFR-Mutant lung cancer; ERK/MAPK signaling pathway; Glutamine metabolism; HHLA2

DOI:  https://doi.org/10.1016/j.canlet.2025.218219
EMBO J. 2025 Dec 17.

The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells.

Niklas Herrle, Pedro F Malacarne, Timothy Warwick, Alfredo Cabrera-Orefice, Yiheng Chen, Maedeh Gheisari, Souradeep Chatterjee, Matthias S Leisegang, Tamim Sarakpi, Sarah Wionski, Melina Lopez, Carine Kader, Tom Teichmann, Maria-Kyriaki Drekolia, Ina Koch, Marcus Keßler, Sabine Klein, Frank Erhard Uschner, Jonel Trebicka, Steffen Brunst, Ewgenij Proschak, Stefan Günther, Mónica Rosas-Lemus, Nina Baumgarten, Stephan Klatt, Thimoteus Speer, Sofia-Iris Bibli, Marta Segarra, Amparo Acker-Palmer, Julian U G Wagner, Ilka Wittig, Stefanie Dimmeler, Marcel H Schulz, J B Richards, Ralf Gilsbach, Travis T Denton, Ingrid Fleming, Luciana Hannibal, Ralf P Brandes, Flávia Rezende.

  Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and identified novel redox-sensitive metabolic enzymes. H2O2 selectively increased the amount of α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and an unrecognized intermediate of endothelial glutamine catabolism. In addition, H2O2 impaired the catalytic activity of nitrilase-like 2 ω-amidase (NIT2), the enzyme that converts αKGM to α-ketoglutarate (αKG), by the reversible oxidation of specific cysteine residues. Moreover, a NIT2 gene variant exhibited decreased expression in humans and was associated with increased plasma αKGM concentration. Endothelial-specific knockout of NIT2 in mice increased cellular αKGM levels and impaired angiogenesis. Further, NIT2 depletion impaired endothelial cell proliferation, sprouting, and induced senescence. In conclusion, we uncover NIT2 as a redox-sensitive enzyme of the glutamine transaminase-ω-amidase pathway that acts as a metabolic switch modulating endothelial glutamine metabolism in mice and humans.

Keywords:  Endothelial Cells; Glutamine Metabolism; Oxidative Stress; α-Ketoglutaramate; α-Ketoglutarate

DOI:  https://doi.org/10.1038/s44318-025-00642-7
bioRxiv. 2025 Dec 10. pii: 2025.12.08.692849. [Epub ahead of print]

Bcl-2 protein Noxa is required for metabolic reprogramming to glutamine dependence and for apoptosis in stimulated human CD8 + T cells.

Tingyuan Yang, Himani Sharma, Jenna M Benson, William J Valente, Rebecca LaRue, Beau Webber, Branden Moriarity, Christopher A Pennell, Stephen C Jameson, Ameeta Kelekar.

Naïve or memory T cells reprogram their metabolism upon antigenic stimulation. They increase their glucose uptake, relying on aerobic glycolysis for generating biomass while switching to glutamine to fuel energy production. Here we have identified a requirement for human Bcl-2 family, Noxa, in the metabolic switch to glutamine dependence in activated CD8 + T cells, that is independent of its canonical role in apoptosis at the end of the immune response. Using an in vitro co-stimulation model, we demonstrate that Noxa is induced in CD8 + T cells and remains elevated during the proliferative and differentiation phases of the response and through the onset of apoptosis. Noxa protein induction requires glutamine, is mediated via mTOR, and is independent of glutaminolysis. Glutamine, in turn, requires Noxa to facilitate its conversion to glutamate. CD8 + T cells lacking Noxa showed reduced levels of intracellular glutamate but no impairment of mitochondrial or effector function, and decreased dependence on glutamine for both respiration and growth during the proliferative phase. NOXA knockout CD8⁺ T cells also displayed significantly higher viability in the apoptotic phase of the immune response. CD8 + T cells from a human NOXA gene-replacement mouse responded normally to in vitro stimulation and in vivo acute infection. However, human Noxa-expressing murine CD8 + T cells displayed a distinctly proliferative gene signature in their transcriptome following activation, supporting an early growth-promoting role for this BH3-only protein. Our studies suggest that knocking out NOXA in human CD8 + T cells to increase their lifespan as well as their ability to survive and function in glutamine-poor microenvironments could be a promising immunotherapeutic strategy.

DOI: https://doi.org/10.64898/2025.12.08.692849
Neurochem Res. 2025 Dec 18. 51(1): 17

L-Theanine Uptake via Solute Carrier Family 38 Member 1 Inhibits Neuroblastoma Cell Growth.

Koichi Kawada, Yuri Matsushima, Ruka Nakamura, Megumi Nishio, Yuka Watanabe, Shuhei Araki, Tamika Sudo, Sayuki Yoshikawa, Mitsuhiro Shibata, Toshihiko Kinjo, Kyosuke Uno, Yutaro Higashiura, Akiko Yamamuro, Yuki Ishimaru, Yasuhiro Yoshioka, Sadaaki Maeda, Nobuyuki Kuramoto.

  L-gamma-glutamylethylamide (L-theanine, theanine) is an amino acid and an umami component found in green tea. According to previous reports, theanine acts on the central nervous system by alleviating stress and maintaining natural sleep. Furthermore, theanine has been reported to have a mild cancer-suppressing effect. However, the molecular mechanism of theanine's potential central nervous system (CNS) activity remains unclear. We evaluated the inhibitory effect of theanine on the proliferation of neural cell lines and found that theanine most effectively inhibited the proliferation of NSC-34 mouse motor neuron-like hybrid cells compared to other neural cells. NSC-34 cell proliferation inhibition by theanine was completely alleviated by co-administration of α-(methylamino) isobutyric acid or leucine, a substrate of solute carrier family 38 member 1 (Slc38a1, the glutamine transporter) or Slc7a5 (the glutamine/leucine exchanger) respectively. This suggests that theanine uptake into cells occurs via Slc38a1 and excretion from cells occurs via Slc7a5. However, inhibition was observed even in the absence of glutamine and did not correlate with changes in mammalian target of rapamycin phosphorylation levels. These results suggest that theanine inhibits proliferation in a manner that is still unclear after it is taken up into cells. Based on these findings, we propose that theanine may exert an inhibitory effect on the proliferation of neural cells that have abnormally proliferating Slc38a1, namely neuroblastoma.

Keywords:  Glutamine; Growth inhibition; L-theanine; Leucine; Slc38a1; Slc7a5

DOI:  https://doi.org/10.1007/s11064-025-04635-0
Metabolism. 2025 Dec 17. pii: S0026-0495(25)00339-7. [Epub ahead of print] 156469

Liver cancer chronically exposed to palmitate acquires ferroptosis resistance via the downregulation of glutamine-driven hepcidin expression.

Dong-Ho Kim, Mi Kyung Kim, Daehoon Kim, Eun-Jun Kwon, Jieun Shin, Sebin Lee, Bae-Gon Kang, Jae Won Yun, Jaebon Lee, Hye Won Lee, Byoung Kuk Jang, Ghilsuk Yoon, Kwang-Hyeon Liu, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

   BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy remains limited. Recent studies demonstrate that resistance to ferroptosis is a significant barrier to the success of ICB.
METHODS: Ferroptosis was assessed by measuring C11-BODIPY fluorescence and 4-hydroxynonenal (4-HNE) staining. Epigenetic regulation of hepcidin under fatty acid-rich conditions in HCC cells was investigated through chromatin immunoprecipitation and histone methylation analyses. Clinical relevance was evaluated using ICB response datasets and analyses of tumor tissues from HCC patients.
RESULTS: We demonstrate that prolonged exposure to high palmitate concentrations induces ferroptosis resistance in HCC cells by altering glutamine availability. Mechanistically, chronic exposure to palmitate and high-fat diet-feeding reduced glutamine-derived α-KG concentrations in HCC cells, leading to a H3K27me3-mediated reduction in hepcidin and depletion of the intracellular labile iron pool, thereby promoting resistance to anti-programmed death-ligand 1 (anti-PD-L1)-induced ferroptosis. This resistance was reversed by the EZH2 inhibitor tazemetostat, which epigenetically restored hepcidin expression in both in vitro and in vivo models. Notably, tumor tissues from HCC patients exhibited high FFA levels, along with low levels of glutamine, hepcidin, and iron, which correlated with shorter overall survival. H3K27me3-mediated suppression of hepcidin was further confirmed in patient cohorts.
CONCLUSION: Our study uncovers a previously unrecognized type of palmitate-induced metabolic reprogramming that confers resistance to ICB-induced ferroptosis on HCC, and propose a therapeutic strategy to overcome ferroptosis resistance under free fatty acid-rich conditions.
ABBREVIATIONS:

Keywords:  Ferroptosis; Glutamine; Hepatocellular carcinoma; Hepcidin; Immune checkpoint blockade; Palmitate

DOI:  https://doi.org/10.1016/j.metabol.2025.156469
Commun Biol. 2025 Dec 13.

Ammonia reduces glutamine synthetase expression in astrocytes via activation of Hippo-YAP signaling pathways.

Yusuke Nasu, Sari Kishikawa, Mamiko Imai, Nozomi Yokoyama, Izumi Iida, Koichi Tabeta, Miho Terunuma.

Glutamine synthetase (GS) expressed in astrocytes plays an important role in maintaining the amount of extracellular glutamate and ammonia in the brain. Deficiency of GS is associated with several neurological disorders including epilepsy, but the molecular mechanism underlying the control of GS expression and the mechanism of GS reduction in diseased brain remain elusive. Here we show that in astrocytes, GS level is regulated by a transcription coactivator YAP via two signaling pathways, the Hippo and Wnt/β-catenin pathways. But when the extracellular glutamate and ammonia are increased, ammonia inhibits YAP nuclear localization through Hippo pathways and reduces GS. Using rodent models of epilepsy, we found that the induction of YAP nuclear translocation with Hippo kinase inhibitor XMU-MP-1 suppresses GS downregulation and protects neurons against cell death. Our work identifies that YAP may become an effective target for diseases in which astrocytic GS is reduced due to elevated ammonia.

DOI: https://doi.org/10.1038/s42003-025-09191-5
Cell Death Dis. 2025 Dec 15.

Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors.

Simona Nicole Barile, Maria Chiara Magnifico, Eleonora Poeta, Felix Distelmaier, Luigi Viggiano, Nicola Balboni, Michele Protti, Sabrina Petralla, Antonella Pignataro, Giacomo Volpe, Monica De Luise, Massimo Bonora, Marica Antonicelli, Giorgia Babini, Francesca Massenzio, Vito Porcelli, Eleonora Lama, Roberto Arrigoni, Isabella Pisano, Veronica Addabbo, Anna Campana, Francesca Begnozzi, Stewart A Anderson, Giuseppe Fiermonte, Federico Manuel Giorgi, Paolo Pinton, Ferdinando Palmieri, Giuseppe Gasparre, Laura Mercolini, Luigi Palmieri, Douglas C Wallace, Julia Hentschel, Barbara Monti, Francesco Massimo Lasorsa.

AGC1 deficiency is a rare, early-onset encephalopathy caused by mutations in the SLC25A12 gene, encoding the mitochondrial aspartate/glutamate carrier isoform 1 (AGC1). Patients exhibit epileptic encephalopathy, cerebral hypomyelination, severe hypotonia, and global developmental delay. A hallmark biochemical feature of AGC1 deficiency is reduced brain N-acetylaspartate (NAA), a key metabolite involved in myelin lipid synthesis. However, the underlying mechanisms leading to the hypomyelinating phenotype remain unclear. In this study, we generated neuronal progenitors (NPs) derived from human-induced pluripotent stem cells (hiPSCs) of AGC1-deficient patients to investigate the metabolic and bioenergetic consequences of AGC1 loss. We demonstrated that AGC1-deficient NPs exhibit impaired proliferation, increased apoptosis, and a metabolic shift toward a hyperglycolytic phenotype due to defective mitochondrial pyruvate oxidation. RNA sequencing revealed downregulation of mitochondrial pyruvate carrier MPC1/2, limiting pyruvate-driven oxidative phosphorylation (OXPHOS) and reinforcing glycolysis as the primary energy source. Despite this metabolic shift, AGC1-deficient mitochondria retained the potential for OXPHOS when alternative anaplerotic substrates were provided. Notably, the administration of ketone bodies, in combination with glutamine, fully restored mitochondrial respiration, suggesting a mechanistic basis for the clinical improvements observed in AGC1-deficient patients undergoing ketogenic diet therapy. Our study highlights the importance of alternative metabolic pathways in maintaining neuronal energy homeostasis in AGC1 deficiency and offers insights into potential therapeutic strategies aimed at bypassing the mitochondrial pyruvate oxidation defect.

DOI: https://doi.org/10.1038/s41419-025-08314-4
Anal Biochem. 2025 Dec 11. pii: S0003-2697(25)00271-4. [Epub ahead of print]710 116032

Identification of the function of the metabolite repair enzyme Nit1: the story of a collaboration with Arthur Cooper.

Emile Van Schaftingen, Alessio Peracchi, Maria Veiga-da-Cunha.

Nit1 and Nit2 were initially identified in the context of cancer research, as proteins encoded by putative (anti)oncogenes. However, the presence of homologous proteins in bacteria suggested that they might be enzymes with a fundamental metabolic function. Our group, while interacting with Arthur Cooper and his collaborators, contributed to uncovering these roles: Nit2 was identified in 2009 as an ω-amidase, the enzyme that hydrolyses the 'ω' amide of α-ketoglutaramate and α-ketosuccinamate, the 'deaminated' derivatives of glutamine and asparagine produced in some irreversible transamination reactions. Later, in 2017, we showed that Nit1 functions as a metabolite-repair enzyme. Specifically, Nit1 efficiently hydrolyzes deaminated gluthathione (dGSH), a non-functional byproduct generated by a side activity of various classical transaminases. This repair function prevents the accumulation of the useless metabolite dGSH. The physiological significance of Nit1 is underscored by recent discoveries linking its deficiency in humans to a neurological disorder.

DOI: https://doi.org/10.1016/j.ab.2025.116032
Life Sci Alliance. 2026 Mar;pii: e202503526. [Epub ahead of print]9(3):

Multi-omics analysis reveals metabolic diversity underlying endothelial cell functions.

Stephan Durot, Peter F Doubleday, Lydia Schulla, Amélie Sabine, Tatiana V Petrova, Nicola Zamboni.

Endothelial cells (ECs) line the vascular system and are key players in vascular homeostasis, yet their metabolic diversity across tissues, vascular beds, and growth states remains poorly understood. This study examines metabolic differences between proliferating and quiescent ECs and compares blood and lymphatic endothelium using proteomics and metabolomics. Our findings indicate that metabolism in quiescent ECs is not dormant but reorganized in a cell-specific manner, with decreased heme intermediates in human umbilical vein ECs and increased branched-chain amino acid catabolism across all quiescent ECs. Consistent with the differences identified in the omics data, perturbation studies revealed that inhibiting enzymes involved in heme, glutamate, fatty acid, and nucleotide biosynthesis led to distinct phenotypic responses in blood and lymphatic ECs. These findings highlight the importance of metabolic pathways in sustaining both proliferating and quiescent ECs and reveal how ECs from different vascular beds rely on distinct metabolic processes to maintain their functional states.

DOI: https://doi.org/10.26508/lsa.202503526