bims-glucam 2025-04-27 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–04–27
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine's double-edged sword: fueling tumor growth and offering therapeutic hope.
Single-cell transcriptomic data reveal the cellular heterogeneity of glutamine metabolism in gastric premalignant lesions and early gastric cancer.
Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.
Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells.
The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma.
Glucose- and glutamine-driven de novo nucleotide synthesis facilitates WSSV replication in shrimp.
DON-Loaded Nanodrug-T Cell Conjugates With PD-L1 Blockade for Solid Tumor Therapy.
Single-cell and spatial transcriptomic insights into glioma cellular heterogeneity and metabolic adaptations.
Embryonic exposure to GenX causes reproductive toxicity by disrupting the formation of the blood-testis barrier in mouse offspring.
Deciphering the Controversial Role of TP53 Inducible Glycolysis and Apoptosis Regulator (TIGAR) in Cancer Metabolism as a Potential Therapeutic Strategy.
A host-pathogen metabolic synchrony that facilitates disease tolerance.
Metabolic Effects of the Cancer Metastasis Modulator MEMO1.
Transformable albumin-based nanocapsules selectively amplify tumor starvation and disulfidptosis through metabolic deception.

Front Immunol. 2025 ;16 1578940

Glutamine's double-edged sword: fueling tumor growth and offering therapeutic hope.

Liguang Fang, Dandan Gao, Zuomin Jiang, Guoliang Li, Ming Li.

  Tumor metabolic reprogramming is a highly complex process that enables tumor survival in the presence of limited nutrients, involving multiple signaling pathways, non-coding RNAs (ncRNAs), and transcription factors. Lately, glutamine has been found to enhance the growth, spread, and drug resistance of cancer cells, while also fostering an immunosuppressive microenvironment that aids tumor development. However, in some tumors, such as pancreatic cancer and melanoma, additional glutamine can inhibit the proliferation of tumor cells, and this mechanism is closely related to the regulation of the immune microenvironment. Therefore, further exploration of glutamine metabolism in tumors is essential for understanding the pathogenesis of cancer and for developing new metabolically targeted therapies. We systematically review the latest research on the reprogramming of glutamine metabolism and its role of tumor growth, spread, and immune system regulation. Additionally, we review the clinical research progress on targeted glutamine therapies and their application in combination with current anti-tumor treatments. Ultimately, we address the challenges and prospects involved in resistance to anti-cancer strategies aimed at glutamine metabolism.

Keywords:  combination therapy; glutamine metabolism; immune microenvironment; metabolic reprogramming; tumors

DOI:  https://doi.org/10.3389/fimmu.2025.1578940
Acta Biochim Biophys Sin (Shanghai). 2025 Apr 23.

Single-cell transcriptomic data reveal the cellular heterogeneity of glutamine metabolism in gastric premalignant lesions and early gastric cancer.

Qingfeng Ni, Jiawei Yu, Yuanjie Niu, Zhenwei Han, Boyang Hu, Yang Wang, Jianwei Zhu.

  Glutamine metabolism is a hallmark of cancer metabolism. This study aims to perform a comprehensive and systematic single-cell profile of glutamine metabolism in premalignant and malignant gastric lesions. We use single-cell transcriptomics data from chronic atrophic gastritis (CAG) and early gastric cancer (EGC) lesions and investigate glutamine metabolism features at the single-cell level. Experiments are implemented to validate the expression and biological role of ERO1LB in gastric cancer (GC). A single-cell atlas based on 22511 cells from premalignant and early-malignant gastric lesions is established. Among these cells, epithelial cells constitute the dominant cell population in both CAG and EGC lesions. The activity of glutamine metabolism is higher in epithelial cells from EGC lesions than in those from CAG lesions. Among the epithelial cell subpopulations, glutamine metabolism is more active in the epithelial cell subpopulation cluster_4 in EGCs than in CAG lesions. As a key marker gene of this subpopulation, ERO1LB is experimentally proven to be overexpressed in human GC tissue lesions. In both in vitro and in vivo experiments, overexpression of ERO1LB in GC cells increases glutamine metabolism, facilitates cell growth and migration and prevents cell apoptosis, and vice versa. This study provides insight into the cellular heterogeneityof glutamine metabolism within the gastric mucosa in premalignant and malignant gastric lesions and identifies ERO1LB as a key orchestrator of glutamine metabolism, which may help to identify markers for GC prevention and contribute to our understanding of GC pathogenesis.

Keywords:  ERO1LB; cellular heterogeneity; chronic atrophic gastritis; gastric cancer; glutamine metabolism; single-cell transcriptomics

DOI:  https://doi.org/10.3724/abbs.2025061
Cell Rep. 2025 Apr 19. pii: S2211-1247(25)00367-5. [Epub ahead of print]44(5): 115596

Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.

Suresh Udutha, Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Meryssa Tran, Johanna Ten Hoeve, Thomas G Graeber, Pavithra Viswanath.

  Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-13C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.

Keywords:  CP: Cancer; CP: Metabolism; TERT; brain tumors; cancer; glioblastoma; glutamine metabolism; glutathione; in vivo stable isotope tracing; metabolic synthetic lethality; metabolomics; nucleotide biosynthesis; telomerase reverse transcriptase

DOI:  https://doi.org/10.1016/j.celrep.2025.115596
Cell Prolif. 2025 Apr 21. e70036

Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells.

Changsen Bai, Jialei Hua, Donghua Meng, Yue Xu, Benfu Zhong, Miao Liu, Zhaosong Wang, Wei Zhou, Liming Liu, Hailong Wang, Yang Liu, Lifang Li, Xiuju Chen, Yueguo Li.

  Glutaminase-1 (GLS1) has garnered considerable interest as a metabolic target in cancer due to its heightened involvement and activity. However, the precise fate of glutaminolysis catalysed by GLS1 in cancer cells remains elusive. We found that GLS1 knockout led to significant suppression of cancer cell proliferation, which can be reversed or partially restored by supplementation of glutamate or non-essential amino acids that can be converted into glutamate. The addition of spliceosomal KGA or GAC ameliorates cancer cell growth in vitro and in vivo, providing both simultaneously completely reverse the effect. The primary metabolic fate of glutamate produced through glutaminolysis in cancer cells is mainly used to produce glutathione (GSH) for redox homeostasis, not entering the tricarboxylic acid cycle or synthesising nucleotides. GSH monoethyl ester (GSH-MEE) effectively rescues the inhibition of cancer cell proliferation caused by GLS1 knockout. Deletion of GLS1 results in an elevation of reactive oxygen species (ROS) and malondialdehyde (MDA), a reduction of NADPH/NADP+ ratio, and an augmented susceptibility of cells to ferroptosis. Glutathione Peroxidase 4 (GPX4) and GPX1 exhibit complementary roles in redox regulation, with GLS1 knockout promoting GPX4 degradation. Pharmacological inhibition of GLS1 synergises with GPX4 inhibitor to suppress tumour growth. Dual targeting of GPX4 and GPX1 presents a potent anti-cancer strategy. This metabolic mechanism facilitates a deeper comprehension of the abnormal glutamine metabolism in cancer cells, establishing a theoretical basis for the potential clinical utilisation of GLS1 inhibitors and presenting novel perspectives for advancing combinatorial therapeutic approaches.

Keywords:  GLS1; GPX4; GSH; cancer cell; ferroptosis; glutamate

DOI:  https://doi.org/10.1111/cpr.70036
Cell Death Discov. 2025 Apr 19. 11(1): 186

The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma.

Yifan Zhang, Shengli Zhang, Hongbin Sun, Luwei Xu.

Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions metabolic reprogramming as a central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, and microenvironment-driven metabolic plasticity. This orchestrated rewiring of cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T cell exhaustion and myeloid-derived suppressor cell activation. Crucially, RCC exhibits metabolic heterogeneity across histological subtypes and intratumoral regions-a feature increasingly recognized as a determinant of therapeutic resistance. Our review systematically deciphers the molecular architecture of RCC metabolism, elucidating how VHL/HIF axis mutations, mTOR pathway dysregulation, and epigenetic modifiers converge to reshape glucose flux, lipid droplet biogenesis, and amino acid catabolism. We present novel insights into spatial metabolic zonation within RCC tumors, where pseudohypoxic niches engage in lactate shuttling and cholesterol efflux to adjacent vasculature, creating pro-angiogenic and immunosuppressive microdomains. Therapeutically, we evaluate first-in-class inhibitors targeting rate-limiting enzymes in de novo lipogenesis and glutamine metabolism, while proposing biomarker-driven strategies to overcome compensatory pathway activation. We highlight the synergy between glutaminase inhibitors and PD-1 blockade in reinvigorating CD8+ T cell function, and the role of lipid-loaded cancer-associated fibroblasts in shielding tumors from ferroptosis. Finally, we outline a translational roadmap integrating multi-omics profiling, functional metabolomics, and spatial biology to match metabolic vulnerabilities with precision therapies.

DOI: https://doi.org/10.1038/s41420-025-02479-9
Cell Commun Signal. 2025 Apr 22. 23(1): 191

Glucose- and glutamine-driven de novo nucleotide synthesis facilitates WSSV replication in shrimp.

Cong-Yan Chen, Chih-Ling Chen, Yen Siong Ng, Der-Yen Lee, Shih-Shun Lin, Chien-Kang Huang, Ramya Kumar, Han-Ching Wang.

   BACKGROUND: Viruses rely on host metabolism to complete their replication cycle. White spot syndrome virus (WSSV), a major pathogen in shrimp aquaculture, hijacks host metabolic pathways to fulfill its biosynthetic and energetic needs. Previous studies have demonstrated that WSSV promotes aerobic glycolysis (Warburg effect) and glutaminolysis during its replication stage (12 hpi). Therefore, glucose and glutamine serve as crucial metabolites for viral replication. Additionally, de novo nucleotide synthesis, including the pentose phosphate pathway and purine/pyrimidine synthesis, is significantly activated during WSSV infection. However, the precise association between WSSV and host glucose and glutamine metabolism in driving de novo nucleotide synthesis remains unclear. This study aimed to investigate the involvement of glucose and glutamine in nucleotide metabolism during WSSV replication and to elucidate how WSSV reprograms these pathways to facilitate its pathogenesis.
METHODS: To assess changes in metabolic flux during WSSV replication, LC-ESI-MS-based isotopically labeled glucose ([U-13C] glucose) and glutamine ([A-15N] glutamine) were used as metabolic tracers in in vivo experiments with white shrimp (Litopenaeus vannamei). The in vivo experiments were also conducted to measure the expression and enzymatic activity of genes involved in nucleotide metabolism. Additionally, in vivo dsRNA-mediated gene silencing was employed to evaluate the roles of these genes in WSSV replication. Pharmacological inhibitors targeting the Ras-PI3K-Akt-mTOR pathway were also applied to investigate its regulatory role in WSSV-induced nucleotide metabolic reprogramming.
RESULTS: The metabolite tracking analysis confirmed that de novo nucleotide synthesis was significantly activated at the WSSV replication stage (12 hpi). Glucose metabolism is preferentially reprogrammed to support purine synthesis, while glutamine uptake is significantly increased and contributes to both purine and pyrimidine synthesis. Consistently, gene expression and enzymatic activity analyses, along with gene silencing experiments, indicated the critical role of de novo nucleotide synthesis in supporting viral replication. However, while the inhibition of the Ras-PI3K-Akt-mTOR pathway suggested its involvement in regulating nucleotide metabolism, no consistent effect on WSSV replication was observed, suggesting the presence of alternative regulatory mechanisms.
CONCLUSION: This study demonstrates that WSSV infection induces specific metabolic reprogramming of glucose and glutamine utilization to facilitate de novo nucleotide synthesis in shrimp. These metabolic changes provide the necessary precursors for nucleotide synthesis, supporting WSSV replication and pathogenesis. The findings offer novel insights into the metabolic strategies employed by WSSV and suggest potential targets for controlling WSSV outbreaks in shrimp aquaculture.

Keywords:  Pentose phosphate pathway; Warburg effect; White shrimp; White spot syndrome virus; de novo nucleotide metabolism; in vivo stable-isotope tracing metabolomics

DOI:  https://doi.org/10.1186/s12964-025-02186-z
Adv Sci (Weinh). 2025 Apr 24. e2501815

DON-Loaded Nanodrug-T Cell Conjugates With PD-L1 Blockade for Solid Tumor Therapy.

Xin Yang, Xiaoshuang Niu, Ye Su, Xiaoyun Ye, Wanqiong Li, Wenxuan Zeng, Xin Zhao, Zhuoying He, Qingyu Dong, Xiuman Zhou, Xinghua Sui, Guanyu Chen, Yanfeng Gao, Juan Liu.

  Adoptive T-cell therapy (ACT) holds significant promise for treating solid tumors but is often constrained by insufficient T-cell infiltration, survival, and functional persistence. To overcome these obstacles, we developed DON-loaded nanodrug-T cell conjugates with PD-L1 blockade, forging a dynamic mutualistic relationship between T cells and therapeutic agents. Sustained release of glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) within these conjugates continuously enhances T-cell endurance and potency by promoting memory differentiation and elevating crucial adhesion and motility genes. Concurrently, PD-L1 blocking peptides liberate T cells from immunosuppression, assisting T cells with precision toward tumor sites. This dual-targeting strategy-T cells directed at tumor antigens and peptides at PD-L1- enriches the tumor microenvironment with potent therapeutics, amplifying T cell-driven tumor destruction. Our approach effectively overcomes the critical barriers of ACT-infiltration, persistence, and efficacy-unlocking the full therapeutic potential of T-cell therapy against complex solid tumors.

Keywords:  Adoptive T‐cell therapy; Cancer immunotherapy; Glutamine metabolism; Solid tumor; T cell‐nanodrug conjugate

DOI:  https://doi.org/10.1002/advs.202501815
Front Immunol. 2025 ;16 1561388

Single-cell and spatial transcriptomic insights into glioma cellular heterogeneity and metabolic adaptations.

Yixin Fu, Yong Yi, Yongxiang Shao, Jingcheng Jiang, Qingshan Deng.

  Glioblastoma, one of the most aggressive and heterogeneous malignant tumors, presents significant challenges for clinical management due to its cellular and metabolic complexity. This review integrates recent advancements in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to elucidate glioblastoma's cellular heterogeneity and metabolic reprogramming. Diverse cellular subpopulations, including malignant proliferative cells, stem-like cells, mesenchymal-like cells, and immune-related cells, contribute to tumor progression, treatment resistance, and microenvironmental interactions. Spatial transcriptomics has further revealed distinct spatial distributions of these subpopulations, highlighting differences in metabolic activities between the tumor core and periphery. Key metabolic adaptations, such as enhanced glycolysis, fatty acid oxidation, and glutamine metabolism, play critical roles in supporting tumor growth, immune evasion, and therapeutic resistance. Targeting these metabolic pathways, especially in combination with immunotherapy, represents a promising avenue for glioblastoma treatment. This review emphasizes the importance of integrating single-cell and spatial multi-omics technologies to decode glioblastoma's metabolic landscape and explore novel therapeutic strategies. By addressing current challenges, such as metabolic redundancy and spatiotemporal dynamics, this work provides insights into advancing precision medicine for glioblastoma.

Keywords:  glioma; metabolic reprogramming; single-cell; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1561388
Toxicology. 2025 Apr 21. pii: S0300-483X(25)00118-0. [Epub ahead of print]515 154161

Embryonic exposure to GenX causes reproductive toxicity by disrupting the formation of the blood-testis barrier in mouse offspring.

Zhencheng Fan, Runyang Hong, Shuhao Li, Liang Kong, Qiyue Zhou, Tan Ma, Hao Chen, Chun Pan.

  As a replacement for perfluorooctanoic acid, hexafluoropropylene oxide dimer acid, commercially referred to as "GenX", has attracted significant attention. However, a comprehensive understanding of the reproductive systems of male offspring exposed to GenX is lacking. This study aimed to investigate how embryonic exposure to GenX affects the reproductive development of male offspring and the underlying mechanisms. We administered GenX daily via gavage (2 mg/kg body weight/day) to the mice from day 12.5 of pregnancy until delivery. Our results suggested that embryonic exposure to GenX led to delayed onset of puberty in male offspring, with destruction of the testicular structure, disruption of the blood-testis barrier, decreased serum testosterone levels, decreased sperm count, impaired sperm motility, and increased rates of sperm abnormalities. We investigated the mechanism of blood-testis barrier breakdown in vitro by treating Sertoli cells (TM4) with GenX. GenX exposure caused the accumulation of senescent TM4 cells, decreased their glutathione (GSH) levels, and increased their oxidized glutathione levels. GenX inhibited glutaminase activity in TM4 cells, leading to decreased GSH synthesis, increased intracellular oxidative stress, and subsequent TM4 cell senescence, ultimately compromising the blood-testis barrier. Our findings indicated that embryonic exposure to GenX may cause Sertoli cell senescence by altering glutamine metabolism, disrupting the blood-testis barrier, and resulting in abnormal reproductive development in male offspring.

Keywords:  Blood-testis barrier; GenX; Offspring; Senescence; Sertoli cells

DOI:  https://doi.org/10.1016/j.tox.2025.154161
Cells. 2025 Apr 15. pii: 598. [Epub ahead of print]14(8):

Deciphering the Controversial Role of TP53 Inducible Glycolysis and Apoptosis Regulator (TIGAR) in Cancer Metabolism as a Potential Therapeutic Strategy.

Fatima I AlMaazmi, Lara J Bou Malhab, Leen ElDohaji, Maha Saber-Ayad.

  Tumor metabolism has emerged as a critical target in cancer therapy, revolutionizing our understanding of how cancer cells grow, survive, and respond to treatment. Historically, cancer research focused on genetic mutations driving tumorigenesis, but in recent decades, metabolic reprogramming has been recognized as a hallmark of cancer. The TP53 inducible glycolysis and apoptosis regulator, or TIGAR, affects a wide range of cellular and molecular processes and plays a key role in cancer cell metabolism by regulating the balance between glycolysis and antioxidant defense mechanisms. Cancer cells often exhibit a shift towards aerobic glycolysis (the Warburg effect), which allows rapid energy production and gives rise to biosynthetic intermediates for proliferation. By inhibiting glycolysis, TIGAR can reduce the proliferation rate of cancer cells, particularly in early-stage tumors or specific tissue types. This metabolic shift may limit the resources available for rapid cell division, thereby exerting a tumor-suppressive effect. However, this metabolic shift also leads to increased levels of reactive oxygen species (ROS), which can damage the cell if not properly managed. TIGAR helps protect cancer cells from excessive ROS by promoting the pentose phosphate pathway (PPP), which generates NADPH-a key molecule involved in antioxidant defense. Through its actions, TIGAR decreases the glycolytic flux while increasing the diversion of glucose-6-phosphate into the PPP. This reduces ROS levels and supports biosynthesis and cell survival by maintaining the balance of nucleotides and lipids. The role of TIGAR has been emerging as a prognostic and potential therapeutic target in different types of cancers. This review highlights the role of TIGAR in different types of cancer, evaluating its potential role as a diagnostic marker and a therapeutic target.

Keywords:  P53; ROS; cancer metabolism; gastric cancer; ketogenic diet; pancreatic cancer; pentose phosphate pathway

DOI:  https://doi.org/10.3390/cells14080598
Nat Commun. 2025 Apr 19. 16(1): 3729

A host-pathogen metabolic synchrony that facilitates disease tolerance.

Ying-Tsun Chen, Gaurav Kumar Lohia, Samantha Chen, Zihua Liu, Tania Wong Fok Lung, Chu Wang, Sebastián A Riquelme.

Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.

DOI: https://doi.org/10.1038/s41467-025-59134-1
Metabolites. 2025 Apr 17. pii: 277. [Epub ahead of print]15(4):

Metabolic Effects of the Cancer Metastasis Modulator MEMO1.

Marziyeh Ghanbarian, Natalia Dolgova, Frederick S Vizeacoumar, Franco J Vizeacoumar, Deborah Michel, Anas El-Aneed, Oleg Y Dmitriev.

  Background/Objectives: Cancer cells often display altered energy metabolism. In particular, expression levels and activity of the tricarboxylic acid cycle (TCA cycle) enzymes may change in cancer, and dysregulation of the TCA cycle is a frequent hallmark of cancer cell metabolism. MEMO1, a modulator of cancer metastasis, has been shown to bind iron and regulate iron homeostasis in the cells. MEMO1 knockout changed mitochondrial morphology and iron content in breast cancer cells. Our previous genome-wide analysis of MEMO1 genetic interactions across multiple cancer cell lines revealed that gene sets involved in mitochondrial respiration and the TCA cycle are enriched among the gain-of-function interaction partners of MEMO1. Based on these findings, we measured the TCA cycle metabolite levels in breast cancer cells with varying levels of MEMO1 expression. Methods: ShRNA knockdown assay was performed to test essentiality of key TCA cycle enzymes. TCA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in MDA-MB-231 (high MEMO1), M67-2 (MEMO1 knockdown), and M67-9 (MEMO1 knockout) cells under iron-depleted, basal iron, and iron-supplemented conditions. Results:ACO2 and OGDH knockdowns inhibit cell proliferation, indicating an essential role of the TCA cycle in MDA-MB-231 metabolism. α-Ketoglutarate and citrate levels exhibited an inverse relationship with MEMO1 expression, increasing significantly in MEMO1 knockout cells regardless of iron availability. In contrast, fumarate, malate, and glutamate levels were elevated in MEMO1 knockout cells specifically under low iron conditions, suggesting an iron-dependent effect. Conclusions: Overall, our results indicate that MEMO1 plays a role in regulating the TCA in cancer cells in an iron-dependent manner.

Keywords:  LC-MS/MS; MEMO1; breast cancer; cancer metastasis; energy metabolism; iron regulation; metal binding protein; tricarboxylic acid cycle

DOI:  https://doi.org/10.3390/metabo15040277
J Control Release. 2025 Apr 19. pii: S0168-3659(25)00359-1. [Epub ahead of print] 113739

Transformable albumin-based nanocapsules selectively amplify tumor starvation and disulfidptosis through metabolic deception.

Yang Li, Yishi Lu, Wei Lu, Nan Zhong, Na Li, Ziqing Xu, Jie Zhang, Hanyao Sun, Feiyun Wu, Zhaogang Teng, Yuxia Tang, Shouju Wang.

  Starvation-based therapy has emerged as a promising approach for cancer treatment. However, tumors can effectively circumvent nutrient deprivation by enhancing the uptake of alternative nutrients such as albumin to attenuate the efficacy of starvation-inducing drugs. In this study, we aimed to exploit the compensatory ability of tumors for alternative nutrients to improve the selectivity of starvation therapy. Albumin nanocapsules were coupled with glucose oxidase (GOX) and loaded with V9302 to obtain nutrient-mimicking transformable nanocapsules (HGV) that induced glucose and glutamine depletion. The HGV entered tumors efficiently owing to their transformability and induced starvation, which in turn upregulated the albumin uptake of the tumors to further increase the internalization of nanocapsules as a positive feedback loop. This amplified starvation led to a significant accumulation of intracellular disulfides and triggered disulfidptosis in the tumor cells, which not only effectively inhibited the growth of primary tumors but also stimulated antitumor immune responses. Furthermore, the tumor selectivity of HGV reduced the hepatotoxicity of GOX and V9302, making it a potential translational starvation-inducing nanocapsule.

Keywords:  Disulfidptosis; Immune modulation; Metabolic deception; Nutrient deprivation; Transformable nanocapsules

DOI:  https://doi.org/10.1016/j.jconrel.2025.113739