bims-glucam 2025-05-25 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–05–25
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

A pathway to sight.
GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells.
Coordination of Glucose and Glutamine Metabolism in Tendon Is Lost in Aging.
Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells.
Glutamine catabolism supports amino acid biosynthesis and suppresses the integrated stress response to promote photoreceptor survival.
ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization.
Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
Antioxidant capacity of the iron-sulfur cluster assembly protein IscU2 is mediated by aspartate metabolism to promote tumor survival.
Defective Endothelial Glutaminolysis Contributes to Impaired Angiogenesis and Poor Ischemic Tissue Repair in Diabetes.
The crosstalk between glutathione metabolism and non-coding RNAs in cancer progression and treatment resistance.
Integrating single-cell and bulk RNA profiles to uncover glutamine metabolism's role in prognosis and immune dynamics in multiple myeloma.
GLS1 promotes lipid metabolism in hepatocellular carcinoma by regulating the PI3K/AKT/mTORC1 signaling pathway through SREBP-1.
Mn-coordination driven glutamine and cancer stemness dual-tailored nano-herb for high-efficiency activation of dendritic cells.
Targeting KRAS Sensitizes Ferroptosis by Coordinately Regulating the TCA Cycle and Nrf2-SLC7A11-GPX4 Signaling in Hepatocellular Carcinoma.
A Missense Substitution in Exon 2 Generates the First HLA-DQB1*04 Allele With Glutamine at Residue 52, DQB1*04:108.
A lncRNA-mediated metabolic rewiring of cell senescence.
Galactose-Functionalized Gold Nanoparticles Targeting Membrane Transporters for the Glutathione Delivery to Brain Cancer Cells.
MYC plus class IIa HDAC inhibition drives mitochondrial dysfunction in non-small cell lung cancer.

Elife. 2025 May 21. pii: e107193. [Epub ahead of print]14

A pathway to sight.

Katherine J Wert.

  The breakdown of glutamine is an important metabolic pathway for the health and survival of rod photoreceptors within the retina.

Keywords:  cell biology; glutaminase; metabolism; mouse; neurodegeneration; neuroscience; photoreceptor; vision

DOI:  https://doi.org/10.7554/eLife.107193
Res Sq. 2025 May 09. pii: rs.3.rs-6480518. [Epub ahead of print]

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

Adriana Ponton-Almodovar, Mary Priyanka 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/10.21203/rs.3.rs-6480518/v1
J Orthop Res. 2025 May 19.

Coordination of Glucose and Glutamine Metabolism in Tendon Is Lost in Aging.

Samuel J Mlawer, Felicia R Pinto, Katie J Sikes, Brianne K Connizzo.

  Tendinopathy is a chronic, degenerative disease that has increased prevalence in aged populations, and is characterized by a loss in extracellular matrix (ECM) integrity. Recent work has clearly demonstrated age-related deficits in ECM synthesis with aging, as well as some changes to metabolic activity. Since glucose metabolism is critical to protein synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We used our previously developed flexor tendon explant model to expose young and aged tendon explants to various concentrations of glucose and glutamine supplementation and observe changes in metabolic activity, matrix composition, matrix biosynthesis, and expression of metabolic and ECM genes. We hypothesized that elevated levels of glucose and glutamine would lead to increased ECM remodeling as well as elevated gene expression of their respective pathways in young tendons, with no such effect in aged tendons. Interestingly, we found that glutamine processing is affected by glucose levels with increased expression of key glutamine processing pathways with increased glucose, but this effect was lost with aging. We also observed that ECM remodeling is directly related to both glucose and glutamine processing with altered glycosaminoglycan and collagen synthesis with glucose and glutamine media concentration. Overall, our work reveals that glucose and glutamine are intricately linked for both tenocyte health and ECM homeostasis and that their metabolism could be one of the key drivers of age-related deficiencies in tissue maintenance.

Keywords:  aging; collagen; mechanobiology; proteoglycans; tendon

DOI:  https://doi.org/10.1002/jor.26100
Cell Signal. 2025 May 15. pii: S0898-6568(25)00289-X. [Epub ahead of print]133 111874

Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells.

Tingyu Chen, Yiming Xu, Fan Yang, Yanxin Pan, Ning Ji, Jing Li, Xin Zeng, Qianming Chen, Lu Jiang, Ying-Qiang Shen.

  Glutamine (Gln), a critical metabolic substrate, fuels the uncontrolled proliferation of cancer cells. Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment, facilitate tumor progression by supplying Gln to cancer cells and driving drug resistance through metabolic reprogramming. This review highlights the key processes of Gln uptake, transport, and catabolism and explores the metabolic crosstalk between CAFs and cancer cells. It also examines the roles of major oncogenic regulators-c-Myc, mTORC, KRAS, p53, and HIF-in controlling Gln metabolism and shaping therapeutic resistance. Current pharmacological approaches targeting Gln metabolism, including enzyme inhibitors and transporter blockers, are discussed alongside emerging therapeutic strategies and ongoing clinical trials. Lastly, we underscore the importance of integrating advanced technologies like artificial intelligence and spatial omics to refine treatment targeting and develop more effective, personalized therapeutic interventions.

Keywords:  Cancer cells; Cancer-associated fibroblasts; Glutamine; Metabolism

DOI:  https://doi.org/10.1016/j.cellsig.2025.111874
Elife. 2025 May 21. pii: RP100747. [Epub ahead of print]13

Glutamine catabolism supports amino acid biosynthesis and suppresses the integrated stress response to promote photoreceptor survival.

Moloy T Goswami, Eric Weh, Shubha Subramanya, Katherine M Weh, Hima Bindu Durumutla, Heather Hager, Nicholas Miller, Sraboni Chaudhury, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Cagri Besirli, Costas A Lyssiotis, Thomas J Wubben.

  Photoreceptor loss results in vision loss in many blinding diseases, and metabolic dysfunction underlies photoreceptor degeneration. So, exploiting photoreceptor metabolism is an attractive strategy to prevent vision loss. Yet, the metabolic pathways that maintain photoreceptor health remain largely unknown. Here, we investigated the dependence of photoreceptors on glutamine (Gln) catabolism. Gln is converted to glutamate via glutaminase (GLS), so mice lacking GLS in rod photoreceptors were generated to inhibit Gln catabolism. Loss of GLS produced rapid rod photoreceptor degeneration. In vivo metabolomic methodologies and metabolic supplementation identified Gln catabolism as critical for glutamate and aspartate biosynthesis. Concordant with this amino acid deprivation, the integrated stress response (ISR) was activated with protein synthesis attenuation, and inhibiting the ISR delayed photoreceptor loss. Furthermore, supplementing asparagine, which is synthesized from aspartate, delayed photoreceptor degeneration. Hence, Gln catabolism is integral to photoreceptor health, and these data reveal a novel metabolic axis in these metabolically demanding neurons.

Keywords:  cell biology; glutaminase; metabolism; mouse; neurodegeneration; neuroscience; photoreceptor

DOI:  https://doi.org/10.7554/eLife.100747
J Exp Clin Cancer Res. 2025 May 19. 44(1): 151

ANXA1 promotes intrahepatic cholangiocarcinoma proliferation and growth by regulating glutamine metabolism through GOT1 stabilization.

Yanyu Gong, Liwen Chen, Hao Wang, Dijie Zheng, Futang Li, Changhao Wu, Yongning Li, Yazhu Deng, Zhiwei He, Chao Yu.

   BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with a poor prognosis, marked by a postoperative recurrence rate of 50-60% and a 5-year survival rate of 8-30%. Abnormal tumor metabolism, particularly, amino acid metabolism, plays a key role in malignant progression. However, the molecular mechanisms linking amino acid metabolism to ICC progression remain unclear.
METHODS: Bioinformatics was used to identity the key amino acid metabolism related gene in ICC, qRT-PCR, western blotting and immunohistochemical (IHC) were used to detect the expression of ANXA1 in normal tissues or ICC tissues and cells at mRNA and protein levels. The effects of ANXA1 on the proliferation ability of ICC in vitro and in vivo were investigated using CCK8, cloning formation experiment, EdU, IHC, nude mice subcutaneous tumorigenesis model. Immunoprecipitation, mass spectrometry analysis, protein ubiquitin level detection test, immunofluorescence co-localization, and redox stress metabolite detection test were used to explore the metabolism-related regulatory mechanism of ANXA1.
RESULTS: we employed bioinformatics analysis to classify ICC into metabolic subgroups with distinct prognoses and identified the associated biomarker Annexin A1(ANXA1), whose high expression is correlated with poor prognosis and promotes ICC development. Mass spectrometry analysis revealed that ANXA1 interacts with the key enzyme in glutamine metabolism, glutamic-oxaloacetic transaminase 1(GOT1). Through in vitro and in vivo experiments, overexpressed ANXA1 stabilizes GOT1 by recruiting the deubiquitinase USP5. This stabilization enhances glutamine uptake, as well as the production of aspartate and glutamate, which in turn reduces oxidative stress, thereby promoting tumor cell growth. Moreover, knockdown of ANXA1 combined with glutamine uptake inhibition significantly suppressed ICC cell proliferation and Inhibited subcutaneous tumor formation and growth.
CONCLUSIONS: These results suggest that the ANXA1/USP5/GOT1 axis promotes glutamine metabolism and ICC proliferation and growth. Inhibiting ANXA1 alongside glutamine uptake inhibition offers a promising strategy for treating ICC.

Keywords:  ANXA1; GOT1; Glutamine metabolism; ICC; Oxidative stress

DOI:  https://doi.org/10.1186/s13046-025-03400-z
Cancer Metab. 2025 May 19. 13(1): 22

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.

Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.

   BACKGROUND: Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+.
METHODS: We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry.
RESULTS: Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition.
CONCLUSIONS: Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

Keywords:  Acute myeloid leukemia; Cancer metabolism; Glycolysis; Lactate dehydrogenase A; NAD+ ; Redox balance

DOI:  https://doi.org/10.1186/s40170-025-00392-4
J Biol Chem. 2025 May 14. pii: S0021-9258(25)02084-8. [Epub ahead of print] 110234

Antioxidant capacity of the iron-sulfur cluster assembly protein IscU2 is mediated by aspartate metabolism to promote tumor survival.

Xunjun Yang, Na Liang, Dandan Liu, Jimei Yan, Xiali Yang, Jinya Lv, Saijun Xiao, Xiujuan Wei, Xuyang Chen, Zhengquan Yang, Shanying Gui, Liqin Jin, Shihui Yu, Jianxin Lyu, Xiaojun Ren.

  Environmental nutrient levels affect cancer cell metabolism, activating adaptive mechanisms in cancer cells to deal with nutrient stress. However, it remains unclear how tumor cells sustain survival under nutrient-stress circumstances through metabolic reprogramming. Our study focused on nutrient deficiency-induced oxidative damage, revealing that increased expression of the iron-sulfur (Fe-S) cluster assembly protein, IscU2, is essential for the survival of pancreatic ductal adenocarcinoma (PDAC) cells in glucose-deficient conditions. Glucose deficiency induces IscU2 expression via the activation of the AMPK pathway, allowing IscU2 to exhibit antioxidant properties that are absent under glucose-sufficient conditions. Upregulated IscU2 stimulates aspartate synthesis by bolstering mitochondrial metabolism, including respiration and the tricarboxylic acid cycle, in a Fe-S cluster-dependent manner. Notably, oxidative stress and apoptosis induced by IscU2 depletion in glucose-deficient PDAC cells can be restored by aspartate-mediated NADPH production. These findings highlight the importance of IscU2 in PDAC cell metabolism and its essential function in supporting cell survival under nutrient-deficient conditions.

Keywords:  Aspartate; Fe-S clusters; IscU2; PDAC; oxidative stress

DOI:  https://doi.org/10.1016/j.jbc.2025.110234
Research (Wash D C). 2025 ;8 0706

Defective Endothelial Glutaminolysis Contributes to Impaired Angiogenesis and Poor Ischemic Tissue Repair in Diabetes.

Meina Zhao, Jiaheng Zhou, Yang Hu, Xinpei Wang, Jiong An, Meijie Liu, Pengfei Zhang, Xing Zhang, Jingwen Wang, Xing Jin, Miaomiao Xi, Jia Li.

It has been demonstrated that glutamine is a key player in boosting endothelial cell (EC) proliferation. However, despite its importance, the role of endothelial glutaminolysis in diabetes remains largely unexplored. Our research aimed to investigate the function of glutaminolysis in ECs within the context of diabetes and to evaluate the potential therapeutic effects of salvianolic acid B (SalB) and α-ketoglutarate (α-KG) on diabetic vascular complications. Histological analysis of skin wounds in diabetic patients revealed delayed restoration of vascularization and collagen synthesis during wound healing, accompanied by decreased glutaminase 1 (GLS1) expression and reduced colocalization with the EC marker platelet-endothelial cell adhesion molecule-1 (CD31). Additionally, a significant decline in GLS1 activity and expression was observed in ECs isolated from diabetic hearts. In vitro studies using cultured ECs demonstrated that exposure to high glucose and high fat (HGHF) reduced GLS1 expression and suppressed glutaminolysis, impairing EC proliferation and tube formation. These adverse effects were mitigated by treatment with SalB or supplementation with α-KG plus nonessential amino acids (NEAAs). Among diabetic mice subjected to myocardial ischemia/reperfusion (MI/R), SalB administration or α-KG supplementation promoted myocardial revascularization and improved cardiac dysfunction. Notably, endothelial-specific GLS1 deletion in mice blocked the beneficial effects afforded by SalB but not those afforded by α-KG. Furthermore, SalB administration accelerated angiogenesis and cutaneous wound healing in diabetic mice, and these influences were removed by pharmacological inhibition of GLS1 using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) or genetic deletion of endothelial GLS1. These findings indicate that defective endothelial glutaminolysis contributes to impaired angiogenesis and poor ischemic tissue repair in diabetes. Improving endothelial glutaminolysis by treatment with SalB or metabolic supplementation with α-KG promotes angiogenesis and ischemic tissue repair in diabetic mice, emphasizing the possibility of GLS1 as a treatment target.

DOI: https://doi.org/10.34133/research.0706
Redox Biol. 2025 May 19. pii: S2213-2317(25)00202-2. [Epub ahead of print]84 103689

The crosstalk between glutathione metabolism and non-coding RNAs in cancer progression and treatment resistance.

Lu Chang, Chao Qin, Jianbo Wu, Haoqin Jiang, Qianqian Xu, Jian Chen, Xiao Xu, Xinju Zhang, Ming Guan, Xuan Deng.

  Excessive reactive oxygen species (ROS) are closely associated with the initiation and progression of cancers. As the most abundant intracellular antioxidant, glutathione (GSH) plays a critical role in regulating cellular ROS levels, modulating physiological processes, and is intricately linked to tumor progression and drug resistance. However, the underlying mechanisms remain not fully elucidated. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of GSH levels. Different ncRNAs modulate various pathways involved in GSH metabolism, and these regulatory targets have the potential to serve as therapeutic targets for enhancing cancer treatment. In this review, we summarize the functions of GSH metabolism and highlight the significance of ncRNA-mediated regulation of GSH in cancer progression, drug resistance, and clinical applications.

Keywords:  Cancer progression; Glutathione metabolism; Resistance; lncRNAs; miRNAs

DOI:  https://doi.org/10.1016/j.redox.2025.103689
BMC Cancer. 2025 May 19. 25(1): 887

Integrating single-cell and bulk RNA profiles to uncover glutamine metabolism's role in prognosis and immune dynamics in multiple myeloma.

Fei Zhao, Feifei Che.

   OBJECTIVE: Multiple myeloma (MM) exhibits significant heterogeneity, leading to variable treatment responses and poor clinical outcomes. Glutamine metabolism-related genes (GMRGs) represent critical regulators of tumor biology, yet their prognostic and therapeutic significance in MM remains unexplored. This study aims to identify GMRG-driven tumor signatures and establish their clinical utility as prognostic biomarkers, therapeutic targets and enhancers of drug sensitivity.
METHODS: Integrated transcriptomic and single-cell sequencing analyses of public multi-omics cohorts enabled systematic identification of GMRGs in MM through weighted co-expression network analysis coupled with univariate Cox proportional hazards modeling. Clinically prioritized GMRGs showing elevated expression in patient specimens were functionally validated through proliferation assays and pharmacological sensitivity profiling.
RESULTS: Integrated multi-omics analysis combining single-cell sequencing with bulk transcriptomic profiling and prognostic screening identified 51 prognostic GMRGs, with 10 core signature genes selected for model construction. The risk stratification system demonstrated robust prognostic capacity validated across multiple independent MM cohorts. Pathway enrichment revealed significant involvement in immune system, cell cycle and tumor signaling. MM patient validation identified DLD, SFT2D2, and UBA2 as significantly upregulated genes that promote tumor growth through enhancement of proliferation. Mechanistic investigations via shRNA-mediated knockdown established that DLD and UBA2 silencing significantly enhanced therapeutic efficacy of MM inhibitors.
CONCLUSION: Multicohort-validated GMRGs (DLD/UBA2) drive MM progression and MM inhibitor responses. Clinical upregulation and functional silencing confirm dual therapeutic potential as prognostic biomarkers and drug-sensitizing targets.

Keywords:  Biomarker; Glutamine metabolism-related genes (GMRGs); Immune infiltration; Multiple myeloma; Prognosis

DOI:  https://doi.org/10.1186/s12885-025-14239-0
Am J Transl Res. 2025 ;17(4): 2527-2540

GLS1 promotes lipid metabolism in hepatocellular carcinoma by regulating the PI3K/AKT/mTORC1 signaling pathway through SREBP-1.

Yaocheng Sun, Ying Shen, Yongmin Yan, Wei Luo, Chuanlei Liu, Jianjun Tang.

   OBJECTIVES: Cancer cells exhibit altered metabolic profiles. Glutaminase 1 (GLS1), a key enzyme in cancer cells, promoting glutamine catabolism to glutamate and ammonia, is strongly associated with various human malignancies.
METHODS: GLS1 promotes lipid accumulation and cell proliferation by upregulating the expression of sterol regulatory element-binding protein 1 (SREBP-1) and SREBP cleavage-activating protein (SCAP). Mechanistically, GLS1 promotes lipid metabolism in HCC cells through the activation of the PI3K/AKT/mTORC pathway.
RESULTS: GLS1's role in lipid metabolism in hepatocellular carcinoma (HCC) remains unexplored. Our findings indicate that GLS1 is not only significantly overexpressed in HCC but also negatively correlates with clinical prognosis. Further investigation revealed that GLS1 drives lipid accumulation and de novo fatty acid synthesis in HCC.
CONCLUSIONS: Our study suggests that GLS1 mediates SREBP-1 to drive lipid metabolism in HCC via the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) signaling pathway, thus we present GLS1 as a potential biomarker and therapeutic target for HCC.

Keywords:  GLS1; Hepatocellular carcinoma; PI3K/AKT/mTORC1 signaling pathway; SREBP-1; lipid metabolism

DOI:  https://doi.org/10.62347/ZTGP5030
Biomaterials. 2025 May 08. pii: S0142-9612(25)00318-7. [Epub ahead of print]322 123399

Mn-coordination driven glutamine and cancer stemness dual-tailored nano-herb for high-efficiency activation of dendritic cells.

Fanchen Yan, Hailong Tian, Shanshan Liu, Jing Zhang, Chen Yang, Lihua Chen, Yaying Zhang, Yuanshen Cao, Yunfeng Song, Canhua Huang, Haiyuan Zhang.

  Dendritic cells (DCs), as specialized antigen-presenting cells, are the commanders of the human immune cell system, directing and controlling various functions of the immune system. However, the competitive plunder of glutamine by tumor cells and the cancer cell stemness significantly impair the functional activation of DCs. Herein, we developed a Mn-coordination driven glutamine and cancer stemness dual-tailored nano-herb (HA/E-M@Purpurin NPs) for high-efficiency activation of DCs. The nano-herb is composed of ellagic acid (EA), divalent manganese ion (Mn2+), and purpurin. EA exerts an inhibitory effect on cell stemness, Mn2+ activate DCs by activating the cGAS-STING pathway, and purpurin inhibits the breakdown of glutamine, leading to a compensatory increase in glutamine content and further activating DCs. After surface modification with hyaluronic acid (HA), the nano-herb can target tumor cells and release drugs to exert corresponding effects. Taken together, our findings underscore the substantial promise of nano-herbs in overcoming cancer stemness-driven immune escape, offering a transformative approach to enhance the success of immunotherapy regimens.

Keywords:  Cancer cell stemness; Cancer immunotherapy; Dendritic cells; Glutaminolysis; Nanoherb

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123399
Smart Med. 2025 Jun;4(2): e70005

Targeting KRAS Sensitizes Ferroptosis by Coordinately Regulating the TCA Cycle and Nrf2-SLC7A11-GPX4 Signaling in Hepatocellular Carcinoma.

Jiaxin Zhang, Zuojia Liu, Wenjing Zhao, Chang Li, Fei Liu, Jin Wang.

  Oncogenic KRAS, a notorious driver of cancer progression, remains a therapeutic challenge. In hepatocellular carcinoma (HCC), KRAS overexpression correlates with tumor aggressiveness. Here, we demonstrate that NSC48160 induces HCC cell death by suppressing KRAS expression. Metabolomic profiling revealed that NSC48160 significantly enhances intracellular tricarboxylic acid (TCA) cycle activity and fructose metabolism, disrupting redox homeostasis, and triggering ferroptosis. Combining NSC48160 with the SLC7A11 inhibitor HG106 synergistically eliminated HCC cells in vitro and suppressed tumor growth in vivo. Mechanistically, NSC48160 indirectly inhibits the Nrf2-SLC7A11-GPX4 axis, as evidenced by ferroptosis-pathway array assays. Specifically, NSC48160 downregulates Nrf2 expression, thereby suppressing its downstream targets GPX4 and SLC7A11, ultimately promoting ferroptosis. Our findings establish NSC48160 as a novel KRAS inhibitor that induces ferroptosis through metabolic and redox reprogramming, offering a promising therapeutic strategy for KRAS-driven HCC.

Keywords:  KRAS; NSC48160; ferroptosis; hepatocellular carcinoma; metabolomics

DOI:  https://doi.org/10.1002/smmd.70005
HLA. 2025 May;105(5): e70265

A Missense Substitution in Exon 2 Generates the First HLA-DQB1*04 Allele With Glutamine at Residue 52, DQB1*04:108.

Juan López-Pérez, Francisco Javier Gil-Etayo, Ariadna Vicente Parra, Isabel Jiménez Hernaz, Amalia Tejeda Velarde.

  HLA-DQB1*04:108, the first HLA-DQB1*04 allele with Glutamine at residue 52 in the peptide-binding domain.

Keywords:   HLA‐DQB1*04:108 ; HLA class II; HLA typing; next‐generation sequencing; peptide‐binding domain

DOI:  https://doi.org/10.1111/tan.70265
Cell Rep. 2025 May 21. pii: S2211-1247(25)00518-2. [Epub ahead of print]44(6): 115747

A lncRNA-mediated metabolic rewiring of cell senescence.

Elena Grossi, Francesco P Marchese, Jovanna González, Enrique Goñi, José Miguel Fernández-Justel, Alicia Amadoz, Nicolás Herranz, Leonor Puchades-Carrasco, Marta Montes, Maite Huarte.

  Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.

Keywords:  CP: Metabolism; CP: Molecular biology; RNA-binding proteins; lncRNA; metabolism; senescence; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.115747
Chembiochem. 2025 May 23. e202500104

Galactose-Functionalized Gold Nanoparticles Targeting Membrane Transporters for the Glutathione Delivery to Brain Cancer Cells.

Francesca Milano, Alessia Nito, Annalisa Caputo, Antonio Gaballo, Marco Marradi, Alessandra Quarta, Andrea Ragusa.

  Glutathione (GSH), a tripeptide essential for maintaining redox balance in the human body, plays a critical role in protecting cells from oxidative stress. A deficiency in GSH is linked to increased oxidative damage and the progression of various disorders, including cancer and neurological diseases. In this study, we developed gold nanoparticles (Au NPs) coated with GSH and further functionalized with galactose moieties to selectively target glucose transporters (GLUT), which is overexpressed on the surface of the blood-brain barrier (BBB) and could be exploited for the selective recognition and internalization of the Au@GSH-Gal NPs, that could then exert an antioxidant effect. As a proof of concept, brain cancer cells were treated with Au@GSH-Gal NPs, evidencing their increased internalization and a significant reduction of H2O2-induced oxidative stress.

Keywords:  Gold nanoparticles; Oxidative Stress; brain cancer cells; galactose transporter; glutathione

DOI:  https://doi.org/10.1002/cbic.202500104
Cell Rep. 2025 May 19. pii: S2211-1247(25)00493-0. [Epub ahead of print]44(6): 115722

MYC plus class IIa HDAC inhibition drives mitochondrial dysfunction in non-small cell lung cancer.

Jina Park, Ying-Yu Chen, Jennie J Cao, Julia An, Ray-Whay Chiu Yen, John D Outen, Stephen B Baylin, Michael J Topper.

  Despite much progress in targeting the MYC oncoprotein, combination treatment strategies are needed to exploit this molecular vulnerability. To this end, we interrogated transcriptome data from cancer cell lines treated with MYC inhibitors and identified HDAC5 and HDAC9, both class IIa histone deacetylases (HDACs), as potential therapeutic targets. Notably, these therapeutically actionable HDAC isoforms are known augmenters of several hallmarks of cancer. Dual targeting of MYC and class IIa HDACs induces a significant reduction in viability for non-small cell lung cancer (NSCLC) cell lines with high MYC and mitochondrial activity. Additionally, combination treatment induces a robust MYC suppression with mitochondrial reactive oxygen species (ROS) elevation, which has a causal relationship with therapeutic efficacy. Confirmation of in vivo efficacy was pursued in several animal models, with subsequent molecular-correlate derivation confirming the importance of MYC depletion and mitochondrial dysfunction in drug efficacy. Ultimately, we define a therapeutic approach combining MYC- and class IIa HDAC-inhibition to potentiate anti-tumor efficacy in NSCLC.

Keywords:  CP: Cancer; MYC; class IIa HDAC; mitochondria; non-small lung cancer; oxidative stess

DOI:  https://doi.org/10.1016/j.celrep.2025.115722