bims-glucam 2025-08-31 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–08–31
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutaminase 1 inhibitors: Therapeutic potential, mechanisms of action, and clinical perspectives.
GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.
Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism.
Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.
GOT2: a moonlighting enzyme at the crossroads of cancer metabolism and theranostics.
Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
Metabolic Reprogramming Shapes the Progression and Therapeutic Landscape of Ovarian Cancer.
Liver regeneration-associated hepatocellular YAP1 activation prevents colorectal cancer liver metastasis through glutamine competition.
Glutamatergic and GABAergic metabolite levels in Alzheimer's disease: a systematic review and meta-analysis.
Metabolic dysregulation in pulmonary fibrosis: insights into amino acid contributions and therapeutic potential.
Hesperetin Protects from Palmitic-Acid-Induced Lipotoxicity through the Inhibition of Glutaminolysis, mTORC1 Signaling, and Limited Apoptosis.
Mode of Action of Toxin 6-Hydroxydopamine in SH-SY5Y Using NMR Metabolomics.
Harnessing PHGDH Inhibition for Cancer Therapy: Mechanisms, SAR, Computational Aspects, and Clinical Potential.
Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response.
S-glutathionylation in cancer: from fundamental mechanisms to clinical applications.
Glutaminolysis impairment and immunometabolic dysregulation in U937 cells: Key mechanisms in occupational and environmental skin exposure to UV and benzo[a]pyrene.
Succinylation - encoded metabolic codes: cracking the molecular logic of cellular adaptation.

Biochem Pharmacol. 2025 Aug 22. pii: S0006-2952(25)00540-4. [Epub ahead of print]242(Pt 1): 117275

Glutaminase 1 inhibitors: Therapeutic potential, mechanisms of action, and clinical perspectives.

Hui Wang, Xiandeng Li, Haitao Hu, Zhan Gao.

  Glutaminase 1 (GLS1) is a critical enzyme in glutamine metabolism, supporting both energy production and biosynthesis in tumor cells. Inhibitors targeting GLS1 have emerged as promising metabolic therapies. Notably, it exhibits antiproliferative and pro-apoptotic effects in various cancers. This review systematically discusses GLS1's structure and function, the major classes of inhibitors, and the principles behind their design. It also explores the molecular mechanisms underlying GLS1 inhibition, including disruption of glutamine metabolism, induction of oxidative stress, and modulation of key signaling pathways. Furthermore, we evaluated the current clinical applications and therapeutic potential of GLS1 inhibitors in cancer and metabolic disorders. Themes such as drug safety, resistance development, and patient stratification are also addressed. Future research should highlight the potential of combination therapies and precision medicine approaches. Collectively, targeting GLS1 represents a promising strategy with significant translational potential in metabolism-related diseases.

Keywords:  Cancer; GLS1; GLS1 inhibitors; Glutamine metabolism; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.bcp.2025.117275
Sci Rep. 2025 Aug 20. 15(1): 30528

GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.

Adriana Ponton-Almodovar, Mary P Udumula, Vrinda Khullar, Faraz Rashid, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.

  Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.

Keywords:  GPT2; Glutamine; Metabolism; Ovarian cancer

DOI:  https://doi.org/10.1038/s41598-025-15707-0
Cell Rep. 2025 Aug 25. pii: S2211-1247(25)00948-9. [Epub ahead of print]44(9): 116177

Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism.

Aprajita Tripathi, Debolina Dasgupta, Michael S Dahabieh, Rachel Griffard-Smith, Anil Pant, Ashlyn Bugbee, Nanda Kumar Yellapu, Emily Burt, Ben H Y Choi, Abigail E Ellis, Ryan D Sheldon, Shailendra Giri, Devin Koestler, Russell G Jones, Viveka Nand Yadav, Kalyani Pyaram.

  Upon antigenic stimulation, CD4+T cells undergo clonal expansion elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid-2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T cells remains unexplored. We report that Nrf2 protein levels are temporally regulated in activated CD4+T cells, with elevated expression during early activation followed by a decline. T cell-specific constitutive activation of Nrf2, by deletion of its negative regulator Keap1, enhances early activation and interleukin-2 (IL-2) expression, upregulates T cell receptor (TCR) signaling, and increases activation-driven expansion of CD4+T cells. Mechanistically, elevated Nrf2 activity in activated CD4+T cells increases chromatin accessibility and proliferation-associated gene expression. Metabolically, high Nrf2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support CD4+T cell hyperproliferation. In summary, we elucidate the role of Nrf2 beyond traditional antioxidation in modulating the activation-driven expansion of CD4+T cells by influencing their nutrient metabolism and gene expression.

Keywords:  CP: Immunology; CP: Metabolism; T cell activation; T cell expansion; adaptive immune cells; antioxidation; immunometabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.116177
Cancer Metab. 2025 Aug 20. 13(1): 38

Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.

Xu Han, Laura C Kim, Nicholas P Lesner, Xuanyan Cai, Tran Ngoc Van Le, M Celeste Simon.

BACKGROUND: Lipid homeostasis is critical for pancreatic adenocarcinoma (PDAC) cell survival under hypoxic and nutrient-deprived conditions. Hypoxia inhibits unsaturated lipid biosynthesis, compelling cancer cells to depend on exogenous unsaturated lipids to counteract saturated lipid-induced toxicity. Our previous work revealed that cancer-associated fibroblasts (CAFs) secrete unsaturated lipids, primarily lysophosphatidylcholines (LPCs), to alleviate lipotoxic stress in PDAC cells. Here, we conducted a drug screen to identify compounds that bypass the rescue effect of exogenous LPCs on cancer cell survival under stress.
METHODS: We employed high-throughput screening of a bioactive chemical library with 3,336 compounds, including FDA-approved drugs and drug-like molecules against defined molecular targets. Two assays were performed: a cytotoxicity assay to exclude indiscriminately toxic compounds at 1 μM and an LPC crosstalk inhibition assay to identify compounds that selectively reduce cancer cell viability in the presence of LPCs under stress conditions.
RESULTS: CB-839, a glutaminase inhibitor, was identified as the most effective compound, selectively inhibiting the LPC-mediated rescue of PDAC cell viability effect without intrinsic cytotoxicity. Mechanistic studies revealed that CB-839 induces cell death by activating the pro-apoptotic ATF4/CHOP pathway, reducing antioxidant production, and increasing reactive oxygen species (ROS). While CB-839 showed limited efficacy against PDAC tumor cells alone in vivo, it modestly inhibited tumor growth in a PDAC-CAF co-implanted subcutaneous mouse model, highlighting its potential to disrupt CAF-mediated nutrient support. Additionally, glutamine antagonists showed more potent tumor-suppressive effects than CB-839.
CONCLUSION: Our findings emphasize the importance of glutamine metabolism inhibition in suppressing tumor growth and disrupting CAF-mediated crosstalk. We further underscore the potential of glutamine antagonist prodrugs as a strategy to target metabolic vulnerabilities in PDAC.

DOI: https://doi.org/10.1186/s40170-025-00389-z
Front Immunol. 2025 ;16 1626914

GOT2: a moonlighting enzyme at the crossroads of cancer metabolism and theranostics.

Junxi Hu, Qingwen Liu, Qinglin Ren, Wenbo He, Jiaqi Hou, Xiaolin Wang, Yusheng Shu.

  Moonlighting enzymes perform multiple distinct functions under different conditions without relying on gene fusion, splicing, or polymerization. Many classical metabolic enzymes, beyond their involvement in pathways like glycolysis and glutamine metabolism, also function as transcription factors, RNA-binding proteins, or signaling molecules. These dual roles are crucial in processes such as cancer metabolic reprogramming, immune evasion, and drug resistance. Glutamate oxaloacetate transaminase 2 (GOT2), a key example, is located in the mitochondria and catalyzes the transamination of aspartate and glutamate. Apart from its metabolic function, GOT2 also influences nuclear fatty acid metabolism and immune-related gene expression, affecting the tumor microenvironment. By integrating metabolic and signaling roles, GOT2 supports tumor cell adaptation to stress, promoting growth, survival, and immune escape. This multifunctionality positions GOT2 as a potential target for cancer diagnosis and therapy. This review discusses GOT2's moonlighting roles and its clinical potential.

Keywords:  GOT2; cancer metabolism; immunotherapy; moonlighting enzymes; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1626914
Nat Commun. 2025 Aug 26. 16(1): 7934

Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.

Xinzhu Li, Ying Zhu, Ting Li, Xinyi Tu, Shiyu Zhu, Lingzhi Wang, Fei Li, Chenglong Sun, Xin Li, Haiyi Zhao, Tang Tang, Qingce Zang, Ruiping Zhang, Zeper Abliz.

Organs collaborate to maintain metabolic homeostasis in mammals. Spatial metabolomics makes strides in profiling the metabolic landscape, yet can not directly inspect the metabolic crosstalk between tissues. Here, we introduce an approach to comprehensively trace the metabolic fate of 13C-nutrients within the body and present a robust computational tool, MSITracer, to deep-probe metabolic activity in a spatial manner. By discerning spatial distribution differences between isotopically labeled metabolites from ambient mass spectrometry imaging-based isotope tracing data, this approach empowers us to characterize fatty acid metabolic crosstalk between the liver and heart, as well as glutamine metabolic exchange across the kidney, liver, and brain. Moreover, we disclose that tumor burden significantly influences the host's hexosamine biosynthesis pathway, and that the glucose-derived glutamine released from the lung as a potential source for tumor glutamate synthesis. The developed approach facilitates the systematic characterization of metabolic activity in situ and the interpretation of tissue metabolic communications in living organisms.

DOI: https://doi.org/10.1038/s41467-025-63243-2
Cancer Manag Res. 2025 ;17 1707-1722

Metabolic Reprogramming Shapes the Progression and Therapeutic Landscape of Ovarian Cancer.

Chunyan Liu, Wenting Liu, Jun Huang, Zhaoying Wu, Wenhui Li, Bo Chen, Yanjun Yang, Hong Lin, Ying Xu.

  Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to its asymptomatic progression, frequent late-stage diagnosis, and high rates of chemoresistance and recurrence. Beyond genetic alterations, recent studies highlight the central role of metabolic reprogramming in driving OC initiation, progression, and therapy resistance. OC cells exhibit dynamic metabolic reprogramming, enabling dynamic shifts between glycolysis and oxidative phosphorylation depending on environmental conditions and treatment pressures. In this review, we synthesize current understanding of key metabolic pathways altered in ovarian tumors, including enhanced aerobic glycolysis, glutamine addiction, dysregulated lipid metabolism, and mitochondrial adaptations. These metabolic shifts support rapid proliferation, redox homeostasis, immune evasion, and metastatic potential. We also explore how the metabolic landscape of OC is shaped by interactions with the tumor microenvironment, particularly through crosstalk with immune cells, cancer-associated fibroblasts, and adipocytes. Importantly, metabolic adaptations have been implicated in the emergence of cancer stem-like cells and in the development of resistance to platinum-based chemotherapy and PARP inhibitors. We also further discuss emerging therapeutic strategies targeting metabolic vulnerabilities, as well as combinatorial approaches integrating metabolic therapy with immunotherapy and DNA damage repair inhibition. Finally, we highlight how advances in metabolomics and spatial profiling are improving our ability to map metabolic heterogeneity and guide precision therapies in OC. This review underscores metabolic plasticity as a promising therapeutic vulnerability for overcoming drug resistance and improving outcomes in OC patients.

Keywords:  cancer stem cells; chemoresistance; metabolic reprogramming; ovarian cancer; tumor microenvironment

DOI:  https://doi.org/10.2147/CMAR.S538281
Sci Adv. 2025 Aug 22. 11(34): eadw6926

Liver regeneration-associated hepatocellular YAP1 activation prevents colorectal cancer liver metastasis through glutamine competition.

Qiang Yu, Mincheng Yu, Peiyi Xie, Lei Guo, Yufei Zhao, Wenxin Xu, Xian Li, Mengyuan Wu, Zihao Zhang, Zheng Chen, Yongsheng Xiao, Jian Zhou, Jia Fan, Mien-Chie Hung, Yongfeng Xu, Bo Zhang, Qinghai Ye, Hui Li.

The literature suggests that hepatocellular Yes-associated protein 1 (YAP1) signaling is activated following hepatectomy and that such activation can suppress the growth of metastatic liver tumors. The prognosis of a real-world cohort of 240 patients with colorectal cancer liver metastasis (CRLM) undergoing major and minor hepatectomy was compared after adjusting for confounding factors. To model CRLM, we induced liver metastasis in mice by transsplenically injecting MC38 cells. We found that patients with CRLM and mice undergoing major hepatectomy had better survival compared to those undergoing minor hepatectomy. Mechanistically, extensive hepatectomy activates hepatocellular YAP1 by regulating the epidermal growth factor receptor, altering glutamine metabolism-related gene expression and increasing liver glutamine consumption. This metabolic shift leads to glutamine scarcity in tumor cells, causing increased reactive oxygen species production, which promotes loss of YAP1 activity in tumor cells. Consequently, the production of the chemokine CXCL5 is suppressed, which inhibits myeloid-derived suppressor cell infiltration and enhancing the immunological function of CD8+ T cells.

DOI: https://doi.org/10.1126/sciadv.adw6926
BMC Neurol. 2025 Aug 26. 25(1): 344

Glutamatergic and GABAergic metabolite levels in Alzheimer's disease: a systematic review and meta-analysis.

Rasoul Ebrahimi, Sana Mohammad Soltani, Mohammad Mahdi Masouri, Mojtaba Seifi, Kiana Ghafourian, Shokoofe Noori.

   BACKGROUND AND OBJECTIVES: This systematic review and meta-analysis compares glutamate, glutamine, and GABA levels in cerebrospinal fluid (CSF), blood, and brain tissue between individuals with Alzheimer's disease (AD) and cognitively unimpaired (CU) controls.
METHODS: We systematically searched PubMed and Web of Science up to February 20, 2025, for studies reporting GABA, glutamate, or glutamine levels in AD and CU controls. Effect sizes were calculated using Hedges' g, with heterogeneity assessed via I² statistics and publication bias evaluated using funnel plots and Egger's and Begg's tests.
RESULTS: From 14,857 records, 53 studies were included. Glutamate levels were significantly lower in AD brains, including the cortex (SMD = - 0.42; 95% CI [-0.79, - 0.05]; I² = 67.26%; p = 0.03), hippocampus (SMD = - 0.56; 95% CI [-0.91, - 0.20]; I² = 37.29%; p < 0.05), and temporal cortex (SMD = - 0.87; 95% CI [-1.52, - 0.23]; I² = 77.60%; p = 0.01), but not in CSF or blood. Glutamine showed no significant differences in brain regions, CSF, or blood. GABA levels were significantly lower in AD patients across the cortex (SMD = - 0.53; 95% CI [-0.81, - 0.25]; I² = 58.60%; p < 0.05), CSF (SMD = - 0.38; 95% CI [-0.65, - 0.11]; I² = 0.00%; p = 0.01), and blood (SMD = - 0.72; 95% CI [-1.08, - 0.37]; I² = 43.18%; p < 0.05).
CONCLUSION: Our findings underscore the potential of targeting glutamatergic and GABAergic systems in AD clinical research. We recommend prioritizing future investigations in earlier disease stages, such as preclinical AD and mild cognitive impairment.

Keywords:  Alzheimer’s disease; GABA; Glutamate; Glutamine; Meta-analysis

DOI:  https://doi.org/10.1186/s12883-025-04375-2
Cell Death Discov. 2025 Aug 27. 11(1): 411

Metabolic dysregulation in pulmonary fibrosis: insights into amino acid contributions and therapeutic potential.

Hongyu Zheng, Lei Zhang, Congjian Wang, Yi Wang, Chenxi Zeng.

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening interstitial lung disease characterized by excessive extracellular matrix deposition and fibroblast activation. Emerging evidence suggests that amino acid metabolism plays a crucial role in the pathogenesis of pulmonary fibrosis. Key amino acids, including arginine, proline, and glutamine, contribute to the regulation of fibroblast activity and collagen synthesis, all of which are essential for fibrotic progression. Studies in experimental models of pulmonary fibrosis have demonstrated significant metabolic dysregulation, further highlighting its relevance in disease development. Moreover, targeting amino acid metabolism has emerged as a promising therapeutic strategy, with novel drugs and interventions designed to modulate metabolic pathways showing potential in preclinical and clinical studies. This review explores the intricate interplay between amino acid metabolism and pulmonary fibrosis, discusses its implications for disease progression, and evaluates the therapeutic prospects of metabolic interventions in IPF management. Understanding these metabolic mechanisms may pave the way for more effective and personalized treatment strategies for IPF.

DOI: https://doi.org/10.1038/s41420-025-02715-2
J Agric Food Chem. 2025 Sep 03. 73(35): 21932-21946

Hesperetin Protects from Palmitic-Acid-Induced Lipotoxicity through the Inhibition of Glutaminolysis, mTORC1 Signaling, and Limited Apoptosis.

Wan Li, Zhengnan Cai, Florian Schindler, Martin Brenner, Christian Winter, Bianca Stiller, Petra Heffeter, Wolfram Weckwerth.

  Palmitic acid-induced lipotoxicity contributes to the development of nonalcoholic fatty liver disease (NAFLD). Hesperetin has been reported to alleviate oxidative stress, inflammation, and cell death in NAFLD, while its potential to mitigate palmitic acid-induced lipotoxicity remains unexplored. This study investigates the protective effects of hesperetin on palmitic-acid-stimulated lipotoxicity and elucidates the underlying molecular mechanisms. Our results showed that hesperetin decreased palmitic acid-activated lipotoxicity through inhibition of the intrinsic apoptosis pathway and promotion of autophagic flux. Metabolomics analysis and stable-isotope-tracing data indicated that hesperetin treatment restored the aberrant tricarboxylic acid cycle caused by palmitic acid exposure, accompanied by a decrease in anaplerotic flux from glutamine to α-ketoglutarate. The reduction of α-ketoglutarate resulted in the inhibition of mTORC1 signaling, which in turn activated autophagy and limited apoptosis. Furthermore, hesperetin activated AMPK, which coordinated with mTORC1 to regulate autophagy. Additionally, hesperetin reinstated the activation of AKT and Nrf2, further protecting the cell against the deleterious effects of lipotoxicity. These data highlight the role of glutaminolysis as a survival mechanism for preventing lipotoxicity upon hesperetin treatment.

Keywords:  glutaminolysis; hesperetin; isotope labeling; lipotoxicity; mTORC1

DOI:  https://doi.org/10.1021/acs.jafc.5c05570
Molecules. 2025 Aug 12. pii: 3352. [Epub ahead of print]30(16):

Mode of Action of Toxin 6-Hydroxydopamine in SH-SY5Y Using NMR Metabolomics.

Roktima Tamuli, George D Mellick, Horst Joachim Schirra, Yunjiang Feng.

  This study used NMR-based metabolomics to investigate the mode of action (MoA) of 6-hydroxydopamine (6-OHDA) toxicity in the SH-SY5Y neuroblastoma cell model. 6-OHDA, a structural analogue of dopamine, has been used to create a Parkinson's disease model since 1968. Its selective uptake via catecholaminergic transporters leads to intracellular oxidative stress and mitochondrial dysfunction. SH-SY5Y cells were treated with 6-OHDA at its IC50 concentration of 60 μM, and samples of treated and untreated groups were collected after 24 h. The endo metabolome was extracted using a methanol-water mixture, while the exo metabolome was represented by the culture media. Further, endo- and exo metabolomes of treated and untreated cells were analysed for metabolic changes. Our results demonstrated significantly high levels of glutathione, acetate, propionate, and NAD+, which are oxidative stress markers, enhanced due to ROS production in the system. In addition, alteration of myoinositol, taurine, and o-phosphocholine could be due to oxidative stress-induced membrane potential disturbance. Mitochondrial complex I inhibition causes electron transport chain (ETC) dysfunction. Changes in key metabolites of glycolysis and energy metabolism, such as glucose, pyruvate, lactate, creatine, creatine phosphate, glycine, and methionine, respectively, demonstrated ETC dysfunction. We also identified changes in amino acids such as glutamine, glutamate, and proline, followed by nucleotide metabolism such as uridine and uridine monophosphate levels, which were decreased in the treated group.

Keywords:  6-OHDA; ETC; NMR metabolomics; ROS; SH-SY5Y

DOI:  https://doi.org/10.3390/molecules30163352
Arch Pharm (Weinheim). 2025 Aug;358(8): e70083

Harnessing PHGDH Inhibition for Cancer Therapy: Mechanisms, SAR, Computational Aspects, and Clinical Potential.

Md Mustahidul Islam, Shivani Kasana, Sakshi Priya, Balak Das Kurmi, Ghanshyam Das Gupta, Preeti Patel.

  3-Phosphoglycerate dehydrogenase (PHGDH) is a key enzyme in the serine biosynthesis pathway, supporting cancer cell growth, survival, and proliferation. Its overexpression is frequently observed in aggressive cancers such as breast cancer, melanoma, and glioma, where it drives tumor growth, metastasis, and resistance to oxidative stress. Targeting PHGDH with small-molecule inhibitors has emerged as a promising therapeutic strategy. Notable inhibitors like NCT-503, CBR-5884, Azacoccone E, and Ixocarpalactone A, along with covalent inhibitors such as Withangulatin A, exhibit potent anticancer activity by limiting serine availability and inducing apoptosis. Gene-silencing techniques, including RNA interference (RNAi) and CRISPR/Cas9, further validate PHGDH as a therapeutic target. Advances in computational methods and structure-activity relationship (SAR) analysis have accelerated the discovery of selective PHGDH inhibitors, offering insights into binding mechanisms and facilitating rational drug design. However, cancer cells can activate alternative metabolic pathways, such as glutaminolysis, to evade PHGDH inhibition. Thus, combination therapies targeting multiple metabolic nodes are being explored to enhance efficacy and overcome resistance. Ongoing research focuses on optimizing PHGDH inhibitors through virtual screening, QSAR modeling, and clinical trials, aiming to integrate them into precision oncology and develop effective therapies for patients with high PHGDH expression or specific metabolic profiles.

Keywords:  PHGDH; cancer metabolism; oxidative stress; serine biosynthesis; targeted therapy

DOI:  https://doi.org/10.1002/ardp.70083
BMC Cancer. 2025 Aug 22. 25(1): 1357

Metabolic landscape of clear cell renal cell carcinoma and search for metabolites predictive of drug response.

Michinobu Ozawa, Sei Naito, Hideki Makinoshima, Hiromi Ito, Atsushi Tsuya, Takafumi Narisawa, Hiroki Fukuhara, Yuki Takai, Masaki Ushijima, Mayu Yagi, Hayato Nishida, Norihiko Tsuchiya.

   BACKGROUND: Clear cell renal cell carcinoma (ccRCC) commonly exhibits biallelic inactivation of VHL genes, profoundly impacting intracellular metabolic pathways and utilization of metabolic substrates. The aims of this study were to validate the metabolomic profile previously identified in ccRCC surgical specimens, to construct a metabolic classification in ccRCC, and to exploratorily investigate metabolic biomarkers of systemic therapy response.
MATERIALS AND METHODS: We first examined the metabolome in 52 paired tumor/normal surgical ccRCC samples, and then compared the metabolites using paired t-test. Unsupervised clustering analysis was done, and the patients were divided into four subgroups. Then tumor grade and transcriptome analyses were compared among the four groups. Finally, to compare the metabolome according to the effect of systemic therapy, we analyzed 9 patients with vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (VEGF-TKI) and 11 patients with immune checkpoint blockade (ICB), respectively.
RESULTS: The upper stream of glycolysis and the pentose phosphate pathway were commonly activated, along with elevated glutamine levels and reduced proteinogenic amino acids (AAs) other than glutamine in ccRCC tissues, consistent with prior findings. Lactate levels, previously reported as elevated, varied across metabolic subgroups. he Metabolic subgroups enriched with high-grade tumors demonstrated lower expression of VEGF pathway-related genes. VEGF-TKI responders showed decreased levels of some fatty acids. ICI responders exhibited reduced levels of tryptophan and hydroquinone. alongside increased levels of pyruvic acid-oxime, 3-hydroxypropinoic acid, and hydroxylamine.
CONCLUSIONS: We validated the landscape of the ccRCC metabolome and identified some metabolites as potential biomarkers for predicting therapeutic response in RCC.

Keywords:  Biomarker; Clear cell renal cell carcinoma; Kidney cancer; Metabolome.

DOI:  https://doi.org/10.1186/s12885-025-14661-4
Pharmacol Res. 2025 Aug 24. pii: S1043-6618(25)00349-4. [Epub ahead of print]220 107924

S-glutathionylation in cancer: from fundamental mechanisms to clinical applications.

Shuai Dong, Li Linghu, Desheng Xiao, Shuang Liu, Yongguang Tao.

  Glutathione (GSH) is a thiol-containing antioxidant composed of glutamic acid, cysteine and glycine. GSH can form a disulfide bond with the cysteine sulfhydryl group of a protein, resulting in S-glutathionylation (-SSG). S-glutathionylation is a reversible posttranslational modification that plays important roles in redox regulation, detoxification, cell signaling pathway regulation, cell death, infection and inflammation. Recent studies have shown that GSH and glutathionylation also have a significant effect on a variety of common cancers. GSH has the potential to serve as an auxiliary diagnostic tool for cancer. S-glutathionylation can regulate the level of the modified protein to regulate tumor cell proliferation and patient survival. In addition, glutathionylation can affect resistance to anticancer clinical drugs, as well as immunotherapy. These findings provide a new therapeutic target for cancer treatment. This review comprehensively reviews the key roles of glutathionylation and its potential mechanisms in a variety of common cancers. Finally, we discuss in depth the role of glutathionylation in resistance to radiotherapy, chemotherapy, targeted drugs and immune checkpoint inhibitors. This study provides a theoretical basis for the development of new cancer treatment drugs.

Keywords:  Cancer; Drug resistance; Glutathione; Glutathionylation

DOI:  https://doi.org/10.1016/j.phrs.2025.107924
Arch Toxicol. 2025 Aug 25.

Glutaminolysis impairment and immunometabolic dysregulation in U937 cells: Key mechanisms in occupational and environmental skin exposure to UV and benzo[a]pyrene.

Christian Kersch, Viktor Masutin, Laura Kuhlmann, Rasha Alsaleh, Andrea Kaifie, Simone Schmitz-Spanke.

  Dermal exposure to polycyclic aromatic hydrocarbons (PAHs) and UV irradiation in occupational and environmental settings poses a health risk by inducing skin toxicity, including immunomodulatory effects. This study investigated the effects of benzo[a]pyrene (B[a]P), a well-characterized PAH, at three concentrations (0.04 nM, 4 nM, and 4 µM) and UV irradiation on human monocytic U937 cells, employing both single and combined exposure scenarios. An integrated metabolomics and toxicological approach was utilized to assess cellular responses, with a focus on understanding the immunometabolic effects of these exposures. Our findings revealed that only the highest B[a]P concentration in combination with UV irradiation resulted in significant metabolic dysregulation and impaired cellular function. Notably, we observed a pronounced downregulation of glutaminolysis, a critical metabolic pathway for cellular energy production and biosynthesis. This was evidenced by decreased levels of glutamate and key intermediates within the tricarboxylic acid cycle (e.g., succinate, fumarate, malate, and citrate), as well as reduced levels of glycine, a precursor for glutathione synthesis. In parallel, toxicological assays revealed increased levels of oxidative stress markers, lipid peroxidation, and enhanced DNA damage. Furthermore, the combined exposure led to alterations in tryptophan metabolism and dysregulation of lipid species, particularly sphingolipids and phosphatidylinositols. These findings lead us to propose the hypothesis that metabolic disruption, specifically the impairment of glutaminolysis, initiated a cascade of events, including increased oxidative stress, lipid peroxidation, and ultimately, ferroptosis in our study. Our results indicate that the combined exposure to UV irradiation and B[a]P can induce immunometabolic reprogramming and significantly contribute to the pathogenesis of inflammatory skin diseases.

Keywords:  Ferroptosis; Glutaminolysis; Immunometabolism; Lipid peroxidation; Lipids; Metabolomics; Monocytes; Polycyclic aromatic hydrocarbons; Skin; UV

DOI:  https://doi.org/10.1007/s00204-025-04155-4
Int J Surg. 2025 Aug 27.

Succinylation - encoded metabolic codes: cracking the molecular logic of cellular adaptation.

Yipeng Cong, Xiaoman Zhang, Zian Wang, Zhongren Cui, Chengming Li, Yongzheng Han, Wen Deng, Xingxuan Zhou, Hongliang Wu, Jingsong Sun, Hongbo Fan, Guangzhen Wu.

   GRAPHICAL ABSTRACT: Lysine succinylation is the covalent modification of succinyl groups (-CO-CH ₂ -CH ₂ -COOH) to lysine residues of target proteins, which causes conformational changes and regulates their functional states. In this figure, mitochondria are used as the metabolic hub to summarize the production and consumption of succinyl-CoA in the TCA cycle and mediate the succinylation of key enzymes and transcription factors such as PDH, SDH, GLUD1, HMGCS2, and FEN1. The central region showed the negative regulation of SIRT5/SIRT7 and the positive regulation of KAT2A, alpha-KGDH, CPT1A, HAT1, and other acyltransferases. The lower part of the figure highlights that succinylation promotes tumor cell hypoxic adaptation and immune escape by stabilizing HIF-1α, inducing ROS production, and SDH dysfunction. TCA, Tricarboxylic acid cycle PDH, Pyruvate dehydrogenase SDH, Succinate dehydrogenase GLUD1, Glutamate dehydrogenase 1 HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2 FEN1, Flap endonuclease 1, SIRT, Sirtuin family proteins, KAT2A, Lysine acetyltransferase 2A alpha-KGDH, Alpha-ketoglutarate dehydrogenase CPT1A, Carnitine palmitoyltransferase 1A HAT1, Histone acetyltransferase 1 HIF-1α, Hypoxia-inducible factor 1 alpha ROS Reactive oxygen species.This figure was created by Biorender.com.(https://BioRender.com).

Keywords:  dessuccinylase tricarboxylic acid cycle; immune escape; succinylation; tumor microenvironment; tumorigenesis

DOI:  https://doi.org/10.1097/JS9.0000000000003249