bims-celmim 2025-09-28 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–09–28
seventeen papers selected by
Marc Segarra Mondejar

The role of fatty acid oxidation in metabolic crosstalk between tumor cells and associated factors in the microenvironment.
Elucidating reaction dynamics in a model of human brain energy metabolism.
The role of succinylation-mediated metabolic reprogramming in tumor progression.
Intracellular pH links energy metabolism to lymphocyte death and proliferation.
Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
A computational model elucidates the effects of oncogene-induced expression alterations on the energy metabolism of neuroblastoma.
Cross-Organ Mitochondrial Communication in Stress and Disease.
Glutamine synthetase shields triple-negative breast cancer cells from ferroptosis in metastasis triggered by glutamine deprivation.
Investigating taurine's biochemical influence in human brain cancer cells with confocal Raman imaging.
Advancements in the Metabolic Profiling of Three-Dimensional Brain Tumor Spheroids for Drug Screening.
Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
An interoceptive model of energy allostasis linking metabolic and mental health.
Purine nucleotides are competitive inhibitors of apo-GOT1.
Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
V-ATPase-dependent induction of selective autophagy.
Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH.
Glioblastoma exploits ATP from leading-edge astrocytes to fuel its infiltrative growth revealed by spatially resolved chimeric analysis.

Biochim Biophys Acta Rev Cancer. 2025 Sep 22. pii: S0304-419X(25)00189-1. [Epub ahead of print] 189447

The role of fatty acid oxidation in metabolic crosstalk between tumor cells and associated factors in the microenvironment.

Suman Pakhira, Subhadip Kundu, Sib Sankar Roy.

  Metabolic reprogramming is a defining characteristic of cancer cells as they undergo multistage development. Cancer cells dynamically adjust their metabolism to aid their survival and to retain their malignant traits within the adverse tumour microenvironment (TME). Fatty acid oxidation (FAO) is a major source of cellular bioenergy, making it a key player in driving cancer cell growth. Over the past few years, an accumulating body of literature has shed light on the role of dysregulated FAO in cancer progression. Besides energy production, FAO also plays a protective role by mitigating lipotoxicity-induced cell death and preventing oxidative stress through NADPH production. Moreover, FAO is intricately linked with numerous critical signaling pathways, substantiating its importance as a pivotal metabolic adaptation in cancer cells. In the TME, various intrinsic and extrinsic factors continuously modulate the behaviour of cancer cells, including their metabolic attributes, such as the activation of FAO. Additionally, alterations in FAO within non-cancerous stromal cells also play a critical role in orchestrating the tumor progression. Despite the emerging recognition of FAO's significance in cancer biology, the precise molecular mechanisms underlying its dysregulation within the TME remain poorly understood. Given the pivotal role of FAO in bioenergetically priming the tumor progression, its aberrant regulation has become a focal point of cancer research, offering potential avenues for novel therapeutic strategies. This review provides an overview of recent advances in understanding how different microenvironmental factors modulate FAO to influence tumor progression.

Keywords:  Fatty acid oxidation; Growth factors; Immune cell metabolism; Metabolic reprogramming; Tumor immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189447
PLoS Comput Biol. 2025 Sep 24. 21(9): e1013504

Elucidating reaction dynamics in a model of human brain energy metabolism.

Dimitris G Patsatzis, Efstathios-Al Tingas, S Mani Sarathy, Dimitris A Goussis, Renaud Blaise Jolivet.

Energy metabolism is essential to brain function, but its study is experimentally challenging. Similarly, biologically accurate computational models are too complex for simple investigations. Here, we analyse an experimentally-calibrated multiscale model of human brain energy metabolism using Computational Singular Perturbation. This approach leads to the novel identification of functional periods during and after synaptic activation, and highlights the central reactions and metabolites controlling the system's behaviour within those periods. We identify a key role for both oxidative and glycolytic astrocytic metabolism in driving the brain's metabolic circuitry. We also identify phosphocreatine as the main endogenous energy supply to brain cells, and propose revising our view of brain energy metabolism accordingly. Our approach highlights the importance of glial cells in brain metabolism, and introduces a systematic and unbiased methodology to study the dynamics of complex biochemical networks that can be scaled, in principle, to metabolic networks of any size and complexity.

DOI: https://doi.org/10.1371/journal.pcbi.1013504
Mol Biol Rep. 2025 Sep 26. 52(1): 954

The role of succinylation-mediated metabolic reprogramming in tumor progression.

Siyi He, Chunduo Wang, Ranran Li, Kexin Xu, Wuzhiyi Zhang, Binbin Feng, Shengtao Cheng, Jihua Ren, Juan Chen.

  Metabolic reprogramming is a hallmark of tumors, whereby cancer cells remodel their own metabolism to meet the biosynthetic, energetic, and signaling demands required for rapid proliferation and malignant transformation. Posttranslational modifications (PTMs) serve as dynamic molecular switches that fine-tune cellular metabolic networks by precisely modulating the activity, stability, and subcellular localization of metabolic enzymes. This regulatory plasticity drives context-dependent metabolic reprogramming in tumor cells, enabling them to adapt to fluctuating physiological demands or pathological stressors while establishing tumor-specific metabolic signatures critical for survival and progression. Among PTMs, lysine succinylation-a recently identified modification catalyzed by succinyl-CoA-has emerged as a critical regulator of cancer metabolism. This unique modification involves the transfer of a negatively charged four-carbon succinyl group to lysine residues, inducing conformational and functional changes in target proteins. Notably, succinylation is evolutionarily conserved across eukaryotes and prokaryotes and has a broad influence on central metabolic pathways, including the tricarboxylic acid (TCA) cycle, amino acid metabolism, and lipid homeostasis. Mounting evidence highlights its dual roles in both sustaining tumorigenic metabolism and directly activating oncogenic signaling cascades. This review summarizes current insights into how succinylation rewires tumor metabolism and delineates its mechanistic contributions to cancer progression.

Keywords:  Cancer; Lysine succinylation; Metabolic reprogramming; Posttranslational modification; Succinyl-CoA

DOI:  https://doi.org/10.1007/s11033-025-11061-6
Sci Rep. 2025 Sep 25. 15(1): 32878

Intracellular pH links energy metabolism to lymphocyte death and proliferation.

Wei-Ping Zeng, Shuangshuang Yang, Baohua Zhou.

The role of intracellular pH (pHi) of lymphocytes in the control of the magnitude of immune response is unknown. The central question addressed in this report is whether energy metabolism affects pHi, which in turn regulates the death and proliferation of the lymphocytes and hence the magnitude of the immune response. To this end, we studied lymphocytes in the in vitro model of anti-CD3 activation and the in vivo mouse model of ovalbumin sensitization and challenge. We found that low pHi induces apoptosis of proliferating lymphocytes, whereas high pHi is conducive to their survival. In the in vivo model, treating the mice with the metabolic regulators dichloroacetate or C75 that increase the influx of carbons derived from pyruvate and fatty acid to the TCA cycle, respectively, lowered pHi. Treatments with the metabolic regulators CB-839 or GSK2837808A that inhibit glutaminolysis and aerobic glycolysis, respectively, also lowered pHi. Proliferation powered by high mitochondrial membrane potentials (MMPs) in lymphocytes of low but not high pHi was accompanied by apoptosis. After antigenic challenge, lymphocytes of high pHi increased and assumed a positive relation between pHi and MMPs, while lymphocytes of low pHi and with an inverse relation between pHi and MMPs diminished. These changes were largely dependent on glutaminolysis and aerobic glycolysis. It is therefore concluded that glutaminolysis and aerobic glycolysis are important for counterbalancing the acidic effects of pyruvate and fatty acid energy metabolism to promote a favorable pHi environment for lymphocyte survival and the progression of the immune response.

DOI: https://doi.org/10.1038/s41598-025-16862-0
Sci Adv. 2025 Sep 26. 11(39): eadt6366

Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.

Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, John D Tranter, Ryan T Mikami, Nihil Abraham, Juan Hong, Ethan Feng, David R Rawnsley, Haiyan Liu, Kayla M Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E Grueter, E Dale Abel, Andrew W Norris, Abhinav Diwan, Rajan Sah.

The lysosome integrates anabolic signaling and nutrient sensing to regulate intracellular growth pathways. The leucine-rich repeat-containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signaling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.

DOI: https://doi.org/10.1126/sciadv.adt6366
Sci Rep. 2025 Sep 24. 15(1): 32708

A computational model elucidates the effects of oncogene-induced expression alterations on the energy metabolism of neuroblastoma.

Mareike Simon, Uwe Benary, Katharina Baum, Alexander Schramm, Jana Wolf.

Alterations in energy metabolism are recognized as a hallmark of cancer. Experimental evidence shows that oncogenes play a key role in the reprogramming of metabolism. In neuroblastoma, the oncogene MYCN, a main risk factor of poor prognosis, has been demonstrated to lead to expression changes in numerous glycolytic enzymes. It is not clear whether all these targets are required and how they jointly shape metabolic responses. Here we use a computational modeling approach to dissect the effects of MYCN targets on the pathway individually and in combination. We develop the first mathematical model of the energy metabolism in neuroblastoma cells based on our published experimental data. The analysis shows that overall, MYCN overexpression leads to Warburg-like flux alterations. However, individual MYCN targets can have opposing and sometimes unexpected effects. Interestingly, not all of them contribute to notable flux alterations, at least with regard to glycolysis. Moreover, our model predicts a potential bistability of cellular metabolism with a low-flux state likely representing a non-proliferative state. Overall, our study emphasizes that perturbations such as expression changes should be analysed in the context of realistic pathway models, in which specific interactions and complex regulations are captured.

DOI: https://doi.org/10.1038/s41598-025-18656-w
Annu Rev Pharmacol Toxicol. 2025 Sep 22.

Cross-Organ Mitochondrial Communication in Stress and Disease.

Koning Shen, Jenni Durieux, Andrew Dillin.

Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1146/annurev-pharmtox-062124-024150
Breast Cancer Res. 2025 Sep 26. 27(1): 165

Glutamine synthetase shields triple-negative breast cancer cells from ferroptosis in metastasis triggered by glutamine deprivation.

Zhaoting Yang, Xinyu Lian, Yuan Luo, Qiao Ye, Guangjin Guo, Guoquan Liu.

   BACKGROUND: Epithelial-mesenchymal transition (EMT) in cancer cell metastasis involves complicated metabolic plasticity to survive the highly challenging environment, such as oxidative stress, after subsequent circulation in the bloodstream. Glutamine synthetase (GS) is an enzyme that converts glutamate and ammonia to glutamine (Gln) during Gln deprivation stress. This study revealed for the first time that GS plays an important role in protecting triple-negative breast cancer (TNBC) cells from ferroptosis during Gln deprivation-induced EMT, namely ferroptosis-resistant EMT (FR-EMT).
METHODS: To better understand this finding, we focused on the mechanism of GS-mediated FR-EMT in TNBC through transcriptomic analysis and murine metastasis modeling.
RESULTS: This study specifically investigated the effects of GS on lipid peroxidation and iron metabolism, the two major metabolic disorders in ferroptosis. An abnormal increase in monounsaturated fatty acids (MUFAs) mediated by mechanistic target of rapamycin complex 1 (mTORC1) decreased the ferroptosis sensitivity under Gln deprivation. Additionally, aberrant iron metabolism via lipocalin 2 (LCN2) and transferrin receptor (TFRC) affected the sensitivity to ferroptosis. Moreover, this study confirmed that GS protects TNBC cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood in the lung metastasis mouse model.
CONCLUSION: This investigation provides insights into the role of ferroptosis in metastasis and demonstrates that GS may be a viable target for preventing metastases in TNBC.

Keywords:  Epithelial-mesenchymal transition; Ferroptosis; Glutamine; Glutamine synthetase; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s13058-025-02115-5
Spectrochim Acta A Mol Biomol Spectrosc. 2025 Sep 20. pii: S1386-1425(25)01261-2. [Epub ahead of print]347 126954

Investigating taurine's biochemical influence in human brain cancer cells with confocal Raman imaging.

Jakub Maciej Surmacki, Krzysztof Sergot.

  Given the widespread use of taurine in energy drinks and nutritional supplements, it is imperative to evaluate its effects on cell behavior and metabolic activity. Understanding the multifaceted cellular effects of taurine remains a significant challenge, particularly in the context of its metabolic and regulatory roles in cancer and stress-adapted cells. One of the limitations in this field has been the lack of imaging techniques capable of capturing taurine's molecular interactions and downstream biochemical alterations in living cells with adequate spatial and molecular specificity. In this study, we employ a Raman-based imaging approach to investigate the intracellular distribution and metabolic consequences of taurine treatment in human brain carcinoma cells (astrocytoma CCF-STTG1 line). This label-free technique enables real-time monitoring of biochemical changes in situ, revealing specific spectral shifts indicative of taurine's influence on energy metabolism, redox balance, lipid dynamics, and structural proteins. We observed marked alterations in Raman spectral bands at ∼750, ∼782, ∼1003, ∼1126, ∼1254, ∼1302, ∼1444, ∼1583, and ∼ 1654 cm-1, which correspond to components such as cytochrome c, nucleic acids, phenylalanine, saturated lipid chains, and amide vibrations of proteins. Notably, the enhancement of cytochrome c signals (∼750 and ∼ 1583 cm-1) suggests an upregulation of mitochondrial oxidative metabolism, while a concurrent attenuation in glycolytic markers (∼870 and ∼ 1450 cm-1) supports a metabolic shift away from aerobic glycolysis. Our Raman spectroscopic findings provide a high-resolution biochemical fingerprint of taurine's intracellular action, offering crucial insights into its role in modulating tumor cell metabolism and potential mechanisms of therapy sensitization. This study contributes to a more precise understanding of taurine's bioactivity in a human brain carcinoma model and underscores the value of vibrational imaging in cellular pharmacology and metabolic research.

Keywords:  Astrocytoma; Brain cancer; Raman spectroscopy and imaging; Taurine

DOI:  https://doi.org/10.1016/j.saa.2025.126954
J Vis Exp. 2025 Sep 05.

Advancements in the Metabolic Profiling of Three-Dimensional Brain Tumor Spheroids for Drug Screening.

Lijing Yang, Xiaojuan Ma, Decao Yang, Jiagui Song, Jianling Yang, Yan Sun, Yan Wang, Lixiang Xue.

Brain tumors, especially gliomas, are challenging to treat because of their aggressive nature, complex tumor microenvironment, and resistance to conventional therapies. Traditional two-dimensional (2D) cell cultures often fail to replicate the true tumor environment, leading to inaccurate predictions of drug efficacy. Extracellular flux analysis technology, typically used for real-time metabolic analysis in 2D cultures, measures key metabolic parameters, such as the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), providing insights into cellular metabolism. The use of 3D models represents a significant advancement, as they more accurately mimic the in vivo tumor environment. The extracellular flux analyzer was adapted to three-dimensional (3D) glioma cell models, enabling the analysis of critical metabolic pathways, including glycolysis and oxidative phosphorylation, in a more physiologically relevant context. U87 cells were seeded at appropriate densities in a 96-well low-attachment plate and cultured for 5 days. On day 5, 3D spheroid formation was observed via high-content imaging. The successfully formed spheroids were then transferred to a metabolic assay plate coated with poly-L-lysine for metabolic analysis. To improve the accuracy of these measurements, high-content imaging systems assess 3D cell size, allowing for precise normalization of extracellular flux data and minimizing metabolic variations due to differences in cell size. This integrated approach provides a more reliable analysis of glioma cell metabolic responses to drug treatments, revealing potential mechanisms of drug resistance. Ultimately, this methodology offers valuable insights into the metabolic dynamics of gliomas and supports the development of novel, clinically relevant therapeutic strategies.

DOI: https://doi.org/10.3791/68833
Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2506417122

Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.

Sara Violante, Aye Kyaw, Lana Kouatli, Kaushik Paladugu, Lauren Apostolakis, Macy Jenks, Amy Johnson, Ryan D Sheldon, Douglas Whitten, Anthony L Schilmiller, Pablo E Visconti, Justin R Cross, Lonny R Levin, Jochen Buck, Melanie Balbach.

  Prior to ejaculation, mammalian sperm are stored in the epididymis in a "resting" metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13C stable isotope labeling in mouse sperm isolated from the cauda epididymis to follow glucose metabolism through central carbon metabolic network before and after sperm activation. As sperm transition from resting to highly activated states, they boost energy yield by increasing flux through glycolysis at the expense of the pentose phosphate pathway. Increased glycolytic activity seems to be achieved via capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the tricarboxylic acid (TCA) cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the flagellum, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase, which also serves to regenerate oxidized nicotinamide adenine dinucleotide (NAD+) ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm, feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating mouse sperm in glucose.

Keywords:  aldolase; glycolysis; metabolic reprogramming; sperm; stable isotope labeling

DOI:  https://doi.org/10.1073/pnas.2506417122
Sci Adv. 2025 Sep 26. 11(39): eady4356

An interoceptive model of energy allostasis linking metabolic and mental health.

Sara Z Mehrhof, Hugo Fleming, Camilla L Nord.

Mental health conditions like depression are associated with an elevated risk of cardiometabolic disorders, yet the mechanisms underlying this comorbidity remain poorly understood. Is metabolic dysfunction a cause of depression, a downstream consequence, or do both stem from shared underlying processes? We argue that neurocognitive mechanisms, particularly those involved in reward and effort processing, interact with metabolic physiology to shape each of these causal pathways. Metabolic signals do not act on the brain in isolation; they are embedded within a broader interoceptive system through which the brain detects and interprets bodily states. This system supports allostasis, the brain's predictive regulation of internal physiological demands. We propose a framework of interoceptive energy allostasis in which disruptions to these predictive processes contribute to the bidirectional relationship between depression and metabolic dysfunction. By integrating perspectives from metabolic and computational psychiatry, this framework offers a theoretical lens to explain the multidirectional comorbidity between mental and metabolic ill-health.

DOI: https://doi.org/10.1126/sciadv.ady4356
bioRxiv. 2025 Sep 17. pii: 2025.09.17.676921. [Epub ahead of print]

Purine nucleotides are competitive inhibitors of apo-GOT1.

Narges Pourmandi, Arjun Jha, Kendall Muzzarelli, Hyunsu Lee, Zahra Assar, Gordon J Murray, Joseph H LaPointe, Thomas P Roddy, Gianna Medeiros, Shomit Sengupta, Costas A Lyssiotis.

The malate-aspartate shuttle (MAS) plays a key role in cellular metabolism by transferring electrons from cytosolic NADH into the mitochondrial matrix, thereby supporting oxidative phosphorylation, in addition to the citric acid cycle and amino acid metabolism. Here, we sought to identify allosteric regulatory metabolites of the MAS enzymes cytosolic glutamic-oxaloacetic transaminase 1 (GOT1) and mitochondrial GOT2. Using the Atavistik Metabolite Proprietary Screening platform, we identified several structurally similar metabolite hits- most notably deoxyadenosine monophosphate (dAMP) and deoxyguanosine monophosphate (dGMP)-as candidate interactors with GOT1. Follow-up thermal shift assays revealed that dAMP and dGMP destabilize GOT1 in the absence of its cofactor, pyridoxal 5'-phosphate (PLP), but have no destabilizing effect when PLP is present. Crystallographic analysis confirmed that dAMP and dGMP bind in the PLP pocket of GOT1, suggesting competitive binding. Together, these results indicate that nucleotide metabolites can interact with GOT1, offering potential insights into MAS regulation and therapeutic intervention strategies.

DOI: https://doi.org/10.1101/2025.09.17.676921
Nat Metab. 2025 Sep;7(9): 1924-1938

Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.

Saloua Benhmammouch, Coraline Borowczyk, Clara Pierrot-Blanchet, Thibault Barouillet, Florent Murcy, Sébastien Dussaud, Marina Blanc, Camille Blériot, Tiit Örd, Lama Habbouche, Nathalie Vaillant, Yohan Gerber, Clément Cochain, Emmanuel L Gautier, Florent Ginhoux, Edward B Thorp, Erik A L Biessen, Judith C Sluimer, Susanna Bodoy, Manuel Palacin, Béatrice Bailly-Maitre, Minna U Kaikkonen, Laurent Yvan-Charvet.

Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.

DOI: https://doi.org/10.1038/s42255-025-01354-2
Nat Commun. 2025 Sep 26. 16(1): 8508

V-ATPase-dependent induction of selective autophagy.

Yuxiang Huang, Dimitra Dialynaki, Yuchen Lei, Zhihai Zhang, Charles R Evans, Daniel J Klionsky.

The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain unclear. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed "V-ATPase-dependent autophagy ". By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that V-ATPase-dependent autophagy is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates V-ATPase-dependent autophagy via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide an explanation for the mutational activation of autophagy seen in follicular lymphoma patients.

DOI: https://doi.org/10.1038/s41467-025-63472-5
Sci Adv. 2025 Sep 26. 11(39): eadx2681

Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH.

Xiaodong Yu, Chenyuan Huang, Martijn Evers, Jingjing Liu, Hui Jun Ting, Sitong Zhang, Suet Yen Chong, Michelle Siying Tan, Siyu Wang, Nilofer Sayed, Liang Gao, Mark D Muthiah, Gwyneth S T Soon, Aileen Wee, Edward Kai-Hua Chow, Natalie Jun Hui Soh, Giorgia Pastorin, Victor C Yu, Bin Liu, Yock Young Dan, Federico Torta, Raymond Schiffelers, Gert Storm, Jiong-Wei Wang.

Increasing evidence implicates ceramides in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). However, the therapeutic potential of liver-targeted ceramide lowering remains unclear. In this study, we demonstrate that elevated ceramide levels in MASH patients and mouse models are closely associated with the activation of hepatic de novo ceramide synthesis. The analysis of human hepatic single-nucleus RNA sequencing (snRNA-seq) data revealed predominant up-regulation of SPTLC2, which encodes a subunit of the rate-limiting enzyme in the de novo ceramide synthesis pathway, in hepatocytes. By targeted inhibition of SPTLC2 with lipid nanoparticle-mediated siRNA delivery to hepatocytes, we reduced both hepatic and circulating ceramide levels. This intervention suppressed hepatic lipid uptake and lipogenesis, thereby alleviating MASH progression. Therapeutic efficacy was demonstrated in an 8-week methionine-choline-deficient diet-induced MASH model and validated in a 1-year choline-deficient high-fat diet-induced MASH model. Our findings highlight hepatocyte Sptlc2 as a promising therapeutic target for MASH.

DOI: https://doi.org/10.1126/sciadv.adx2681
Sci Adv. 2025 Sep 26. 11(39): eadv5673

Glioblastoma exploits ATP from leading-edge astrocytes to fuel its infiltrative growth revealed by spatially resolved chimeric analysis.

Gaoxia Yang, Xiaodong Niu, Jieying Gan, Tianping Yu, Menghan Li, Peng Xiao, Rui Zhang, Ping He, Yuan Yang, Yi Cui, Xiaoyi Huang, Yuan Wang, Qing Mao, Ran Zhou.

Glioblastoma (GBM) is the deadliest primary brain tumor that frequently infiltrates surrounding brain tissue, causing therapy resistance and recurrence. The molecular characteristics of infiltrating GBM cells and their interactions with brain cells remain poorly understood, partly due to limited spatial tools for distinguishing tumor cells from those in the tumor microenvironment (TME). Here, we introduce Spatially-resolved Chimeric AnalyzeR (SCAR), a computational tool for dissecting tumor-TME gene expression in spatial transcriptomics of human-mouse chimeric cancer models. SCAR reveals spatially distinct characteristics of GBM and their interactions with TME, identifying that infiltrative GBM up-regulates creatine kinase brain type (CKB) at the astrocyte-enriched leading edge compared to the tumor core. Mechanistically, GBM-secreted CKB catalyzes the extracellular conversion of astrocyte-supplied adenosine triphosphate (ATP) and creatine into phosphocreatine, providing metabolic support for infiltrative tumor growth, which can be blocked by cyclocreatine. These results provide proof-of-concept validation of SCAR and demonstrate spatial context-dependent metabolic rewiring of GBM cells, with implications for therapies targeting infiltrative GBM.

DOI: https://doi.org/10.1126/sciadv.adv5673