bims-glucam 2025-07-20 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–07–20
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

The Cold Atmospheric Plasma Inhibits Cancer Proliferation Through Reducing Glutathione Synthesis.
Adaptively increased intake of arginine sustains oral keratinocyte survival through alleviating oxidative stress during targeting glutamine metabolism.
Enhanced LDL uptake and PPARα signaling support OSCC cell survival under glutamine deprivation.
Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment.
Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition.
Metabolic reprogramming: The driving force behind cancer drug resistance.
The role of deiodinases on metabolic alteration in cancer.
The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism.
Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer.
Characterization of WAC interactions with R2TP and TTT chaperone complexes linking glucose and glutamine availability to mTORC1 activity.
High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency.
Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.
SLC1A5-dependent glutamine uptake in hepatocytes promotes liver regeneration.
Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.
Lipids: Driving Forces in the Underlying Biology of Carcinogenesis.
Multi-omics analysis reveals glutathione metabolism-related immune suppression and constructs a prognostic model in lung adenocarcinoma.

Molecules. 2025 Jun 30. pii: 2808. [Epub ahead of print]30(13):

The Cold Atmospheric Plasma Inhibits Cancer Proliferation Through Reducing Glutathione Synthesis.

Qiyu Yang, Wei Zhao, Lingling Yang, Yongqin Fan, Changsheng Shao, Tao Wang, Fengqiu Zhang.

  (1) Objective: Cold atmospheric plasma (CAP) is a safe and effective alternative to radiotherapy for cancer treatment. Its anticancer effects are attributed to increased intracellular reactive oxygen species (ROS). Glutathione, a key antioxidant derived from glutamine, is critical for cell proliferation. This study investigated whether CAP-induced ROS elevation results from reduced glutamine-glutathione conversion and elucidates the underlying mechanisms. (2) Methods: Using esophageal squamous carcinoma cell models (Ec9706 and Eca109), we analyzed CAP's effects on key enzymes in glutamine metabolism (Glutaminase 1 and γ-glutamylcysteine ligase) and proliferation-related genes (e.g., Retinoblastoma and Nuclear respiratory factor 2). Transcriptome analysis further explored molecular pathways involved in CAP-mediated anticancer effects. (3) Results: CAP reduced Glutaminase 1 and γ-glutamylcysteine ligase expression, leading to lower intracellular glutathione, higher ROS activity, and enhanced apoptosis. Transcriptome data confirmed CAP's role in oxidation-reduction reactions and glutamine metabolism. (4) Conclusions: This study provides the first mechanistic insights into CAP's anticancer effects by targeting glutamine metabolism. While based on in vitro assays, these findings guide the development of novel CAP therapies for currently incurable cancers.

Keywords:  cancer; cold atmospheric plasma; esophageal squamous carcinoma; glutamine metabolism; glutathione

DOI:  https://doi.org/10.3390/molecules30132808
Biochem Pharmacol. 2025 Jul 12. pii: S0006-2952(25)00430-7. [Epub ahead of print] 117165

Adaptively increased intake of arginine sustains oral keratinocyte survival through alleviating oxidative stress during targeting glutamine metabolism.

Chao Lv, Haoan He, Mi Lin, Wei Li, Wenxin Mu, Bin Cheng, Xiaoan Tao.

  Glutamine is a crucial amino acid with a variety of important roles in both health and disease, with ASCT2 (alanine-serine-cysteine transporter 2)-mediated uptake being critical for cellular homeostasis. While ASCT2 inhibition has been proposed as a therapeutic strategy for oral malignancies, our prior work revealed its paradoxical pro-tumorigenic effects in oral squamous cell carcinoma (OSCC), underscoring the complexity of glutamine metabolism targeting. Here, we identify a compensatory arginine-dependent survival mechanism in oral epithelial cells under glutamine restriction. ASCT2-knockout mice exhibit homeostasis in proliferation and apoptosis through SLC7A2 (solute carrier family 7 member 2) upregulation, a process driven by ROS/NF-κB signaling. Increased intracellular arginine serves as an effector for mTOR/S6 activation to promote cell growth in response to glutamine restriction. Additionally, arginine uptake could effectively alleviate oxidative stress and reduce cell apoptosis via the synthesis of glutathione (GSH) and the activation of NRF2/HO-1 signaling upon ASCT2 knockdown. These results not only delineate the metabolic reprogramming cascade mediated through ASCT2 suppression, but more importantly, reveal a clinically actionable strategy of dual glutamine-arginine metabolic intervention with translational promise for overcoming therapy resistance across multiple pathological states, particularly in malignancies exhibiting metabolic plasticity.

Keywords:  ASCT2; Arginine; Glutamine; ROS; SLC7A2

DOI:  https://doi.org/10.1016/j.bcp.2025.117165
Med Oncol. 2025 Jul 14. 42(8): 332

Enhanced LDL uptake and PPARα signaling support OSCC cell survival under glutamine deprivation.

Luyao Cai, Yutong Chen, Shouyi Tang, Qing Wang, Yiming Xu, Yanxin Pan, Fan Yang, Tingyu Chen, Qianming Chen, Yu Zhou, Ying-Qiang Shen.

  Oral squamous cell carcinoma (OSCC) urgently requires innovative therapeutic strategies due to its severity and stagnant five-year survival rate. Targeting glutamine metabolism, a promising approach, is hampered by tumor cells' profound metabolic plasticity. Through a series of experiments, we uncovered heterogeneous responses of OSCC cell lines to glutamine deprivation: While most cells maintained growth, HSC3 cells showed a marked reduction in proliferation. Subsequent experiments have shown that this slowdown was not due to programmed cell death. Metabolomics and biochemical assays revealed elevated cholesterol ester (ChE) levels in glutamine-tolerant cells, not due to enhanced endogenous synthesis (HMGCS1/SQLE expression decreased) but via upregulated low-density lipoprotein receptor (LDLR)-mediated LDL uptake. Moreover, we found that fatty acid oxidation during glutamine deprivation not only supplied substrates for the tricarboxylic acid (TCA) cycle but also accelerated energy metabolism and potentially increased lipid synthesis for membrane structure and signaling. RNA sequencing identified robust enrichment of the peroxisome proliferator-activated receptor α (PPARα) pathway in tolerant cells. Reactive oxygen species (ROS) accumulation and activating transcription factor 5 (ATF5) nuclear translocation suggested the activation of multiple stress response pathways to maintain survival and growth under glutamine deprivation. Our study reveals a survival mechanism in OSCC: cells enhance exogenous lipid utilization to bypass glutamine dependence. Combined inhibition of LDL uptake and PPARα signaling may overcome metabolic plasticity, providing a rationale for precision therapies targeting metabolic heterogeneity in OSCC.

Keywords:  Glutamine deprivation; LDL; OSCC; PPARα

DOI:  https://doi.org/10.1007/s12032-025-02867-2
Adv Biol (Weinh). 2025 Jul 13. e00738

Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment.

Tianhe Li, Sepehr Akhtarkhavari, Sumeng Qi, Jiawei Fan, Tu-Yung Chang, Yao-An Shen, JinMing Yang, Barbara S Slusher, Ie-Ming Shih, Stephanie Gaillard, Tian-Li Wang.

  Targeting glutamine metabolism has emerged as a promising strategy in cancer therapy. To attain clinical utility, a number of challenges must be overcome, including in vivo anti-tumor activity, pharmacological toxicity, and clinical safety. Aside from glutamine-addicted tumor cells, immune cells may also need glutamine to sustain physiological activities; thus, the current work used two immunological-intact murine cancer models to assess the effects of glutamine antagonists on tumor cells and the immune milieu. To minimize potential off-target effects, we developed a glutamine antagonist prodrug, JHU083, which is bioactivated selectively in cancer tissues. In both murine tumor models, we observed a significant anti-tumor effect, resulting in reduced tumor burden and impeded tumor progression. Single-cell RNA sequencing of tumor tissues demonstrated that JHU083 significantly hampered the immunosuppressive M2-like macrophages but not the pro-inflammatory M1-like macrophages. Expression of Myc- and hypoxia-regulated genes were also inhibited by JHU083. Ex vivo bone marrow-derived macrophage cultures further confirmed that M2 macrophages were more sensitive to glutamine antagonist than M1 macrophages. Together, our findings indicate that JHU083 exerted its anti-tumor activity not only through direct targeting of glutamine-addicted cancer cells but also by shifting the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.

Keywords:  JHU083; chemoresistance; endometrial cancer; glutamine metabolism; immunocompetent model; ovarian cancer; tumor macrophages

DOI:  https://doi.org/10.1002/adbi.202400738
J Proteome Res. 2025 Jul 17.

Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition.

Enzhi Luo, Neeraj Manvi Agarwal, Junjeong Choi.

  Tamoxifen (TAM) is a frontline therapy for luminal A breast cancer, yet acquired resistance poses a significant clinical challenge. This study investigates the molecular and metabolic basis of TAM resistance in MCF7/Tam1 cells, focusing on EPAS1 (HIF-2α)-driven hypoxia-induced metabolic reprogramming and the potential of the EPAS1 inhibitor PT2977 to restore TAM sensitivity. Comparative transcriptomic analysis revealed upregulation of EPAS1 along with enrichment of hypoxia-associated pathways, including JAK-STAT, TGF-beta, and lipid metabolism in resistant cells. Untargeted LC-MS/MS metabolomics identified 1,039 significantly altered metabolites, with notable dysregulation in glutamate and glutathione metabolism, the Warburg effect, and fatty acid oxidation. Mechanistically, EPAS1 promoted fatty acid uptake via CD36 and enhanced glutamine metabolism through SLC1A5, contributing to redox balance and cell survival under TAM stress. Treatment with PT2977 disrupted these metabolic pathways, as evidenced by PCA and Venn analyses, leading to a dose-dependent normalization of metabolite profiles and selective reduction in cell viability. These findings highlight EPAS1-mediated metabolic reprogramming as a key driver of TAM resistance and support EPAS1 inhibition by PT2977 as a promising therapeutic strategy to overcome resistance in luminal A breast cancer.

Keywords:  EPAS1; PT2977; hypoxia; metabolomics.; tamoxifen resistance

DOI:  https://doi.org/10.1021/acs.jproteome.5c00170
Semin Oncol. 2025 Jul 16. pii: S0093-7754(25)00084-3. [Epub ahead of print]52(5): 152392

Metabolic reprogramming: The driving force behind cancer drug resistance.

Amr Ali Mohamed Abdelgawwad El-Sehrawy, Chou-Yi Hsu, Ali G Alkhathami, Muktesh Chandra, Tina Saeed Basunduwah, H Malathi, Jitendra Narayan Senapati, Apurav Gautam, Mundher Kadhem, Hatif Abdulrazaq Yasin.

  Metabolic reprogramming enables stress adaptation of cancer cells to treatment and is a primary causative force of drug resistance. Dysregulation of glucose, amino acid, and lipid metabolism supplies energy, biosynthetic precursors, and redox balance, promoting survival in the treated tumor. These processes are coordinated by oncogenic signaling, loss of tumor suppressors, and regulatory non-coding RNAs, which promote cancer stemness, immune evasion, and resistance to apoptosis. This review examines the mechanisms by which central metabolic pathways, particularly glycolysis, glutamine metabolism, and fatty acid synthesis, are altered to facilitate drug resistance in various types of cancer. Additionally, we report on novel therapeutic approaches that exploit such metabolic weaknesses to prevent therapy resistance and enhance clinical outcomes. Future directions emphasize the need for advanced metabolic profiling to personalize treatment approaches and the clinical translation of promising preclinical findings to overcome this significant obstacle in cancer therapy.

Keywords:  Cancer metabolism; Drug resistance; Metabolic inhibitors; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152392
Semin Cancer Biol. 2025 Jul 10. pii: S1044-579X(25)00096-3. [Epub ahead of print]114 215-226

The role of deiodinases on metabolic alteration in cancer.

Caterina Miro, Annunziata Gaetana Cicatiello, Monica Dentice, Annarita Nappi.

  Deiodinases are key regulators of Thyroid Hormone (TH) bioavailability, exerting a precise spatial and temporal control over T3 levels in peripheral tissues. By dynamically modulating TH activation and inactivation, deiodinases allow target organs to adapt TH signaling to physiological and pathological demands, highlighting their importance in both health and disease. In cancer, their dysregulated expression reprograms cellular metabolism and shapes the tumor microenvironment (TME). Type 3 deiodinase (D3), frequently upregulated in proliferative and hypoxic tumor regions, fosters cell proliferation and resistance to differentiation. Conversely, type 2 deiodinase (D2) sustains glycolytic metabolism, angiogenesis, and redox disbalance, particularly in aggressive and p53-deficient tumors. Beyond cancer cells, deiodinases activity influences stromal and immune compartments, impacting glutamine metabolism and immune cell plasticity. This complex endocrine-metabolic axis supports tumor adaptation to stress and contributes to the emergence of resistance to therapy. Recent advances reveal the potential of targeting deiodinases to counteract cancer metabolic reprogramming and re-sensitize tumors to treatment. Given the essential and multifaceted roles of deiodinases in cancer biology, a comprehensive understanding of their mechanisms of action, regulation, and clinical implications is critical. This review aims to summarize current knowledge on the roles of deiodinases in cancer metabolism and immunity, focusing on their biochemical properties, regulatory networks, tissue-specific functions, and contributions to disease. In doing so, we seek to highlight emerging concepts in local TH signaling and explore potential avenues for therapeutic intervention targeting deiodinase pathways in precision oncology.

Keywords:  Cancer metabolism; Deiodinases; Glutamine addiction; Metabolic reprogramming; Thyroid Hormone

DOI:  https://doi.org/10.1016/j.semcancer.2025.07.003
Mol Metab. 2025 Jul 15. pii: S2212-8778(25)00115-2. [Epub ahead of print] 102208

The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism.

Joanna Krawczyk, William O'Connor, Pedro Vendramini, Mareike Schell, Kiran J Biddinger, Matt Kanke, George Pengo, Ivana Semova, Tiffany Fougeray, Marcia Haigis, Krishna G Aragam, Wouter H Lamers, Linus T Tsai, Praveen Sethupathy, Sudha B Biddinger.

  TCF7L2 harbors the strongest genetic association with diabetes identified thus far. However, its function in liver has remained unclear. Here, we find that liver-specific deletion Tcf7l2 has little effect on plasma glucose, but disrupts hepatic zonation. That is, in the normal liver, many genes show gradients of expression across the liver lobule; in the absence of Tcf7l2, these gradients collapse. One major consequence is the disorganization of glutamine metabolism, with a loss of the glutamine production program, ectopic expression of the glutamine consumption program, and a decrease in glutamine levels. In parallel, metabolomic profiling shows glutamine to be the most significantly decreased metabolite in the plasma of individuals harboring the rs7903146 variant in TCF7L2. Taken together, these data indicate that hepatic TCF7L2 has a secondary role in glycemic control, but a primary role in maintaining transcriptional architecture and glutamine homeostasis.

Keywords:  Zonation; diabetes; metabolism; transcription

DOI:  https://doi.org/10.1016/j.molmet.2025.102208
J Transl Med. 2025 Jul 17. 23(1): 803

Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer.

Jiannan Chen, Lianfeng Zhao, Wenying Li, Shuai Wang, Jiayi Li, Zhongyuan Lv, Yaoyao Zhao, Junqing Liang, Zhigang Hu, Feiyan Pan, Lingfeng He, Lili Gu, Zhigang Guo.

   BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy holds promise for cancer treatment, but its efficacy is often hindered by metabolic constraints in the tumor microenvironment. This study investigates the role of glutamine in enhancing CAR-T cell function against ovarian cancer.
METHODS: Metabolomic profiling of blood samples from ovarian cancer patients treated with MSLN-CAR-T cells was conducted to identify metabolic changes. In vitro, glutamine pretreatment was applied to CAR-T cells, and their proliferation, CAR expression, tumor lysis, and cytokine production (TNF-α, IFN-γ) were assessed. Mechanistic studies focused on the mTOR-SREBP2 pathway and its effect on HMGCS1 expression, membrane stability and immune synapse formation. In vivo, the antitumor effects and memory phenotype of glutamine-pretreated CAR-T cells were evaluated.
RESULTS: Elevated glutamine levels were observed in the blood of ovarian cancer patients who responded to MSLN-CAR-T cell treatment. Glutamine pretreatment enhanced CAR-T cell proliferation, CAR expression, tumor lysis, and cytokine production. Mechanistically, glutamine activated the mTOR-SREBP2 pathway, upregulating HMGCS1 and promoting membrane stability and immune synapse formation. In vivo, glutamine-pretreated CAR-T cells exhibited superior tumor infiltration, sustained antitumor activity, and preserved memory subsets.
CONCLUSIONS: Our findings highlight glutamine-driven metabolic rewiring via the mTOR-SREBP2-HMGCS1 axis as a strategy to augment CAR-T cell efficacy in ovarian cancer.
TRIAL REGISTRATION: NCT05372692.

Keywords:  CAR-T cell therapy; Glutamine; HMGCS1; MTOR-SREBP2 Axis; Ovarian cancer; T cell exhaustion

DOI:  https://doi.org/10.1186/s12967-025-06853-0
FEBS Open Bio. 2025 Jul 13.

Characterization of WAC interactions with R2TP and TTT chaperone complexes linking glucose and glutamine availability to mTORC1 activity.

Sofía Cabezudo, Natalia Cuervo, Carmen García-Martín, Andrés López-Perrote, Clara Reglero, Adrián Maqueda-Real, Ana González-Corpas, Marina Serna, Diego Megías, Alejo Efeyan, Solip Park, Oscar Llorca.

  TELO2-TTI1-TTI2 (TTT) and R2TP are multi-subunit chaperones that cooperate with HSP90 to assemble matured complexes of the PIKK family of kinases, including mTOR complex 1 (mTORC1). WAC, a protein previously implicated in transcription, H2B ubiquitination, and autophagy, was recently identified as a regulator of mTORC1 in response to glucose and glutamine availability, acting in concert with R2TP and TTT. However, the molecular basis of the interactions of WAC with R2TP and TTT and their role in mTORC1 regulation remains poorly defined. Here, we characterized the interactions of WAC with mTOR, R2TP, and TTT and how these are affected by nutrient conditions. Using purified proteins, we establish that WAC directly binds to mTOR-mLST8, R2TP, and TELO2, but not TTI1 and TTI2. In cells, WAC is part of complexes containing components of mTORC1, R2TP, and TTT, and these associations are modulated by nutrient availability. Notably, WAC and TELO2 strongly associate with mTOR under glucose and glutamine deprivation, and these interactions are weakened minutes after nutrient refeeding. These dynamics correlate with changes in mTORC1 activity. Transcriptomic and proteomic analysis shows that WAC, mTOR, R2TP, and TTT are co-expressed across several human cancers, supporting that WAC is part of a functional pathway with mTOR, R2TP, and TTT. Together, our findings reveal the formation and disassembly of a WAC complex with mTOR and TELO2 that contributes to regulate mTORC1 in response to glucose and glutamine availability.

Keywords:  R2TP; RUVBL1‐RUVBL2; TELO2; WAC; mTORC1

DOI:  https://doi.org/10.1002/2211-5463.70085
bioRxiv. 2025 Jun 11. pii: 2024.12.14.628525. [Epub ahead of print]

High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency.

Swati Dubey, Simran Rai, Fabiola Guillen, Ajeeth Iyer, Su Aung, Ming Yuan, Charles G Eberhart, Fausto J Rodriguez.

Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy and radiotherapy, are limited by resistance mechanisms and formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report the results of a high-throughput screening of 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent ATRX and NF1 loss. Among the screened compounds, K784-6195 (ChemDiv ID) emerged as a promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 µM). In comparison, wild-type ATRX sporadic glioma cell lines (U251) exhibited significantly reduced sensitivity to K784-6195 (IC50 = 37.03 µM). However, ATRX knockout U251 glioma cells recapitulating concurrent ATRX and NF1 loss exhibited heightened susceptibility to K784-6195 (IC50 = 20-23 µM) compared to their wild-type counterpart. Metabolomic analysis revealed that K784-6195 treatment impairs metabolic pathways, including the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, leading to oxidative stress and impaired cell survival. These findings highlight K784-6195 as a promising candidate for therapeutic development, offering a targeted approach for the treatment of NF-1 associated HGGs with ATRX deficiency.

DOI: https://doi.org/10.1101/2024.12.14.628525
J Exp Med. 2025 Sep 01. pii: e20241426. [Epub ahead of print]222(9):

Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.

Xiaoyun Li, Sofie Hedlund Møller, Jaeoh Park, Yu-Ming Chuang, Pei-Chun Hsueh, Tzu-Hsuan Chang, Kung-Chi Kao, Hector Gallart-Ayala, Yi-Hao Wang, Jhan-Jie Peng, Alessio Bevilacqua, Yi-Ru Yu, Zhiyu Li, Yann Kieffer, Domitille Peigney, Hugo Croizer, Yingxi Xu, Alfred Zippelius, Isabel C Lopez-Mejia, Lluis Fajas, Fatima Mechta-Grigoriou, Julijana Ivanisevic, Zhengtao Xiao, Ming-Chih Ho, Ying-Chun Shen, Ping-Chih Ho.

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared with normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs) and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving TLR4, Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.

DOI: https://doi.org/10.1084/jem.20241426
Hepatol Commun. 2025 Aug 01. pii: e0742. [Epub ahead of print]9(8):

SLC1A5-dependent glutamine uptake in hepatocytes promotes liver regeneration.

Yunhao Duan, Sheng Peng, Jinnan Yue, Fan Ding, Xiaoli Chen, Wenqi Pan, Xiaotong Gao, Peilin Pang, Yuting Zhang, Wenrun Wu, Kai Markus Schneider, Francisco Javier Cubero, Christian Trautwein, Lin Zhang, Yuzhen Zhang, Jie Liu, Gang Zhao.

   BACKGROUND: The liver's remarkable regenerative capacity after injury restores essential functions for maintaining homeostasis. Understanding molecular circuits initiating liver regeneration leads to new therapies. Solute carrier family 1, member 5 (SLC1A5) is a key glutamine transporter crucial for hepatocyte proliferation. This study investigates the role of SLC1A5 in hepatocytes during liver regeneration and explores its underlying mechanisms.
METHODS: We retrieved a hepatocyte-RNA sequencing dataset from mice post-PHx (GSE181761) and a single-nucleus-RNA sequencing dataset from human livers (GSE223561). THLE-2 human hepatocyte cell line was used to study SLC1A5 function in vitro, while magnetic nanoparticles carrying thyroxine-binding globulin (TBG)-promoter-driven Slc1a5 gRNA-Cas9 plasmids were administered to mice for hepatocyte-specific Slc1a5 deletion, enabling in vivo investigation.
RESULTS: We identified 58 significantly altered SLC family genes in hepatocytes post-PHx. A subset of 29 genes, selected based on q value, was linked to L-glutamine transmembrane transporter activity via Gene Ontology functional enrichment analysis, as well as glutamine secretion and L-glutamine import across the plasma membrane by Gene Ontology biological process enrichment analysis. Among these enriched genes, Slc1a5 emerged as the most critical gene regulating glutamine activity, with the highest expression observed in proliferating cyclin-positive hepatocytes. Slc1a5 upregulation on day 2 post-PHx was confirmed in vivo, with increased glutamine uptake and cyclin gene expression in proliferating hepatocytes during liver regeneration. Targeted delivery of Slc1a5-gRNA nanoparticles for hepatocyte-specific gene deletion significantly reduced glutamine uptake, hepatocyte proliferation, and impaired liver regeneration in both PHx and CCl4 injury models.
CONCLUSIONS: Together, SLC1A5 in hepatocytes facilitates glutamine uptake, upregulates cyclin gene expression, and promotes hepatocyte proliferation and liver regeneration.

Keywords:  hepatocytes; liver regeneration; magnetic nanoparticles; single-cell RNA sequencing; solute carrier family 1 member 5 (SLC1A5)

DOI:  https://doi.org/10.1097/HC9.0000000000000742
bioRxiv. 2025 May 09. pii: 2025.05.05.652119. [Epub ahead of print]

Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.

Sung Hoon Cho, Shawna K Brookens, Ariel L Raybuck, Kaylor Meyer, Yeeun C Paik, Jennie Hamilton, Jingxin Li, Karel Kalecky, Chloe Park, Sakeenah L Hicks, John Karijolich, Teodoro H Bottiglieri, Jeffrey C Rathmell, Denis Mogilenko, Chris D Scharer, Mark R Boothby.

The efficiencies with which activated B lymphocytes proliferate and develop into antibody (Ab)- secreting plasma cells are critical determinants of adaptive humoral immunity and central to sustaining certain autoimmune diseases. Increasing evidence indicates that specific pathways in intermediary metabolism, or their substrate supply, influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases proliferation and differentiation of B cells into plasma cells, glutaminolysis - a major means of metabolism of this amino acid - was only conditionally crucial in B cells and the Ab responses derived from them. Strikingly, Gls , the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases only when either glucose uptake into B cells or pyruvate into their mitochondria was also impaired. This synthetic auxotrophy involved support to a progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel not only decreased the coupling of IL-21 stimulation to STAT3 induction, but also interferon stimulation of STAT1 activation. Together, our findings establish not only a powerful collaboration of metabolic pathways in promoting increased respiration and the development of Ab-secreting cells, but also a capacity of metabolism to modulate cytokine receptor signaling.

DOI: https://doi.org/10.1101/2025.05.05.652119
ACS Pharmacol Transl Sci. 2025 Jul 11. 8(7): 1891-1918

Lipids: Driving Forces in the Underlying Biology of Carcinogenesis.

Sohini Chakraborty, Anudarshini Sathish Kumar, Satarupa Banerjee.

  Lipids, mainly composed of cholesterol, phospholipids, sphingolipids, triacylglycerides, and fatty acids, have vital functions within cells. Some lipids function as signaling molecules or secondary messengers and are cellular membranes' energy sources and structural elements. More research is being conducted on metabolic reprogramming as a hallmark of cancer. However, compared with the metabolism of glucose or glutamine, lipid metabolism in cancer has received less attention. There is increasing evidence that certain parts of the lipid metabolism are altered in cancer cells. The alterations could influence the quantity of lipids involved in signaling functions, affect the synthesis and breakdown of lipids necessary for maintaining energy homeostasis, and modify the availability of structural lipids critical for membrane formation. The term "lipid metabolic reprogramming" refers to modifications in the lipid metabolism that can impact cellular processes such as cell division, growth, proliferation, and the cell cycle, ultimately resulting in cancer. Furthermore, interactions between cancer cells and nearby immune cells via an altered lipid metabolism promote the development and spread of tumors. The most recent studies on the involvement of lipid metabolism in different cancers and associated hallmarks and lipids in various aspects of cancer therapeutics, which affect multiple facets of tumorigenesis, are described in this review.

Keywords:  and; cancer hallmarks; lipid droplets and rafts; lipid reprogramming; lipogenic factors; therapeutics; treatment resistance

DOI:  https://doi.org/10.1021/acsptsci.5c00170
Front Immunol. 2025 ;16 1608407

Multi-omics analysis reveals glutathione metabolism-related immune suppression and constructs a prognostic model in lung adenocarcinoma.

Yuxiang Chi, Guoyuan Ma, Qiang Liu, Yunzhi Xiang, Defeng Liu, Jiajun Du.

   Background: Metabolic reprogramming within the tumor microenvironment plays a pivotal role in tumor progression and therapeutic responses. Nevertheless, the relationship between aberrant glutathione (GSH) metabolism and the immune microenvironment in lung adenocarcinoma, as well as its clinical implications, remains unclear.
Methods: We leveraged genome-wide association study (GWAS) data and applied genetic causal analysis to evaluate the causal relationships among plasma 5-oxoproline levels, lung adenocarcinoma (LUAD) risk, and 731 immune phenotypes. We incorporated single-cell RNA sequencing data from LUAD to compare transcription factor activity, cell communication networks, and CD8+ T cell subset distributions across distinct GSH metabolic groups, followed by pseudotime analysis. Whole-transcriptome data from the TCGA database were analyzed for functional enrichment, immune infiltration, and immune functionality. Prognostic genes were identified using WGCNA and LASSO-Cox regression, and the expression was validated via qRT-PCR. Thereafter, immunotherapeutic efficacy and drug sensitivity were predicted using the TIDE platform and the oncoPredict package. A prognostic model was constructed to forecast patient survival, which was further validated in two independent GEO datasets.
Results: Genetic causal analysis indicated a positive correlation between plasma 5-oxoproline levels and LUAD risk. ScRNA-seq analysis revealed an increased proportion of exhausted CD8+ T cells in the high GSH metabolic group, accompanied by altered transcription factor activity and distinct cell communication patterns. Furthermore, whole-transcriptome data analysis demonstrated that patients with a high metabolic phenotype exhibited significantly diminished immune functionality and overall immune infiltration. Using WGCNA and LASSO-Cox regression, we ultimately identified three key genes (LCAL1, RHOV, and MARCHF4) and generated a gene risk score. This score effectively predicts both immunotherapy response and drug sensitivity. qRT-PCR confirmed the upregulation of MARCHF4 in LUAD cells. In addition, stratification by gene risk scores revealed significant differences in immune cell infiltration, immunotherapeutic response, and drug sensitivity. The nomogram model demonstrated strong predictive accuracy in both the TCGA cohort and two independent GEO validation datasets.
Conclusions: GSH metabolic reprogramming may suppress antitumor immunity by modulating transcription factor activity, remodeling cell communication networks, and regulating CD8+ T cells. The prognostic risk model developed herein effectively predicts immunotherapeutic response, drug sensitivity, and overall survival in patients with LUAD.

Keywords:  glutathione metabolism; immunotherapy; multi-omics; prognostic model; single-cell sequencing

DOI:  https://doi.org/10.3389/fimmu.2025.1608407