bims-glucam 2025-03-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–03–02
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting Metabolic Vulnerabilities to Combat Drug Resistance in Cancer Therapy.
Metabolic Regulation by p53: Implications for Cancer Therapy.
Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
Fluorescence Assisted Investigation of ERK1/2 Signaling in the Regulation of ATG3 and ATG5 Under Glutamine and Glucose Deprivation in Breast Cancer Cells.
The Role of HK2 in Tumorigenesis and Development: Potential for Targeted Therapy with Natural Products.
Transcriptomics insights into glutamine on repairing of histamine-induced Yak rumen epithelial cells barrier damage in vitro.
Male proband with intractable seizures and a de novo start codon disrupting variant in GLUL.
Targeting amino acid metabolism to inhibit gastric cancer progression and promote anti-tumor immunity: a review.
Plant-derived terpenoids modulating cancer cell metabolism and cross-linked signaling pathways: an updated reviews.
Divergent Requirements for Glutathione Biosynthesis During Osteoclast Differentiation In Vitro and In Vivo.
A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.
A prognostic signature of Glutathione metabolism-associated long non-coding RNAs for lung adenocarcinoma with immune microenvironment insights.
Glutamate decarboxylase confers acid tolerance and enhances survival of mycobacteria within macrophages.
Recent Advances in Glutathione Depletion-Enhanced Porphyrin-Based nMOFs for Photodynamic Therapy.
Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.
Characterization of the glutathione redox state in the Golgi apparatus.
Systems-level design principles of metabolic rewiring in an animal.

J Pers Med. 2025 Jan 27. pii: 50. [Epub ahead of print]15(2):

Targeting Metabolic Vulnerabilities to Combat Drug Resistance in Cancer Therapy.

Taranatee Khan, Manojavan Nagarajan, Irene Kang, Chunjing Wu, Medhi Wangpaichitr.

  Drug resistance remains a significant barrier to effective cancer therapy. Cancer cells evade treatment by reprogramming their metabolism, switching from glycolysis to oxidative phosphorylation (OXPHOS), and relying on alternative carbon sources such as glutamine. These adaptations not only enable tumor survival but also contribute to immune evasion through mechanisms such as reactive oxygen species (ROS) generation and the upregulation of immune checkpoint molecules like PD-L1. This review explores the potential of targeting metabolic weaknesses in drug-resistant cancers to enhance therapeutic efficacy. Key metabolic pathways involved in resistance, including glycolysis, glutamine metabolism, and the kynurenine pathway, are discussed. The combination of metabolic inhibitors with immune checkpoint inhibitors (ICIs), particularly anti-PD-1/PD-L1 therapies, represents a promising approach to overcoming both metabolic and immune evasion mechanisms. Clinical trials combining metabolic and immune therapies have shown early promise, but further research is needed to optimize treatment combinations and identify biomarkers for patient selection. In conclusion, targeting cancer metabolism in combination with immune checkpoint blockade offers a novel approach to overcoming drug resistance, providing a potential pathway to improved outcomes in cancer therapy. Future directions include personalized treatments based on tumor metabolic profiles and expanding research to other tumor types.

Keywords:  cancer; drug resistance; immunometabolism; oxidative metabolism; tumor metabolism

DOI:  https://doi.org/10.3390/jpm15020050
Mol Cells. 2025 Feb 20. pii: S1016-8478(25)00022-6. [Epub ahead of print] 100198

Metabolic Regulation by p53: Implications for Cancer Therapy.

Ki Yeon Koo, Kwanho Moon, Hwa Seob Song, Min-Sik Lee.

  The tumor suppressor p53, long known for its roles in maintaining genomic integrity and suppressing tumorigenesis, has recently been recognized as a key regulator of cellular metabolism. Here, we review p53's emerging metabolic functions, highlighting its ability to orchestrate glucose, amino acid, and lipid metabolism. By promoting oxidative phosphorylation while inhibiting glycolysis and anabolic pathways, wild-type p53 counters metabolic reprogramming characteristic of cancer cells, such as the Warburg effect, and protects cells from mild cellular stresses. In contrast, mutant p53 disrupts these processes, fostering metabolic adaptations that support tumor progression. These findings pave the way for therapeutic approaches targeting p53-driven metabolic vulnerabilities in cancer.

Keywords:  Cancer metabolism; Metabolic reprogramming; Tumor suppressor; p53 (TP53)

DOI:  https://doi.org/10.1016/j.mocell.2025.100198
J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00198-X. [Epub ahead of print] 108349

Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.

Emma C Rowland, Matthew D'Antuono, Anna Jermakowicz, Nagi G Ayad.

  Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. Therefore, we must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY. We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and shifts the cellular metabolic profile towards oxidative stress and cell death. Mechanistically, MAT2a and AHCY regulate spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevent oxidative damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM. Significance We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM has the potential to reduce tumor growth and improve survival in patients.

Keywords:  glioblastoma; lipid peroxidation; metabolism; metabolomics; methionine; mitochondria; oxidative stress

DOI:  https://doi.org/10.1016/j.jbc.2025.108349
Luminescence. 2025 Mar;40(3): e70132

Fluorescence Assisted Investigation of ERK1/2 Signaling in the Regulation of ATG3 and ATG5 Under Glutamine and Glucose Deprivation in Breast Cancer Cells.

G Gokulapriya, B S Lakshmi.

  Extracellular signal-regulated kinases (ERKs) belong to the family of mitogen-activated protein kinases and transmit extracellular signals. The present study investigates ERK-mediated control of ATG3 and ATG5 as an adaptive response to glutamine and glucose deprivation, with the ERK-CREB axis implicated in this regulatory mechanism. Hyperactivation of ERKs plays a major role in tumor progression and differentiation. Phosphorylation of ERK1/2 at Thr202/Tyr204 residues was higher during glutamine and glucose starvation. Inhibition of ERK1/2 reduced cell viability, increased the presence of acidic vesicular organelle as observed by acridine orange fluorescence staining, and enhanced the expression levels of ATG3 and ATG5 proteins, signifying the protective role of ERK1/2 through control of ATG3 and ATG5 during starvation. The transcription factor CREB is activated by various kinases, including ERKs. Phosphorylation at Serine133 enables CREB to carry out transcriptional activation. Inhibition of ERK1/2 decreased CREB expression, suggesting that ERK1/2-dependent activation of CREB contributes to a reduction in cell viability and upregulation of ATG3 and ATG5 during glutamine and glucose starvation. Our findings collectively suggest that the ERK-mediated control of ATG3 and ATG5, in association with CREB, is essential for maintaining cell viability, serving as a stress adaptive strategy during glutamine and glucose starvation.

Keywords:  ATGs; ERK1/2; breast cancer; fluorescence; nutrient deprivation

DOI:  https://doi.org/10.1002/bio.70132
Int J Med Sci. 2025 ;22(4): 790-805

The Role of HK2 in Tumorigenesis and Development: Potential for Targeted Therapy with Natural Products.

Keren He, Fangfang Tao, Yangyuxiao Lu, Mengqi Fang, Hong Huang, Yuan Zhou.

  Hexokinase 2 (HK2) is widely distributed in various tissues, particularly showing significantly elevated expression levels in tumor tissues. As the initial rate-limiting enzyme in the glycolysis process, HK2 is believed to directly participate in the metabolic reprogramming of tumor cells. This phenomenon, known as the "Warburg effect," provides the energy and substances necessary for the rapid proliferation, growth, and division of tumor cells. Furthermore, by enhancing glycolysis, HK2 exerts its influence on various metabolic pathways in tumor cells, such as pentose phosphate metabolism, glutamine metabolism, serine metabolism, and glycine metabolism, thereby playing a role in the occurrence and development of cancer. Therefore, HK2 represents a promising target for cancer therapy. Simultaneously, natural products with effects on inhibiting the expression or activity of HK2, have already been discovered to exhibit significant anticancer potential. Flavonoids, pentacyclic triterpenoids, phenolic compounds, and lignans constitute the majority of these natural products, directly inhibiting HK2 or indirectly downregulating it through protein kinase B (AKT), hypoxia-inducible factor 1 alpha (HIF-1α), and c-Myc signaling pathways. However, several challenges remain, such as further screening for natural products that directly target and inhibit HK2, optimizing the selection of natural product inhibitors for HK2, and elucidating the molecular mechanisms by which natural products indirectly inhibit HK2. In conclusion, the potential of targeting HK2 for cancer therapy is promising, and with these challenges addressed, natural products inhibiting HK2 will play an even greater role in the fight against cancer.

Keywords:  Anticancer; Glycolysis; Hexokinase 2; Natural products; Therapeutic target

DOI:  https://doi.org/10.7150/ijms.105553
BMC Genomics. 2025 Feb 25. 26(1): 195

Transcriptomics insights into glutamine on repairing of histamine-induced Yak rumen epithelial cells barrier damage in vitro.

Xiaohong Zhang, Rui Hu, Zhisheng Wang, Junmei Wang, Ziqi Yue, Fali Wu, Wenjuan Zhou, Ali Mujtaba Shah.

   BACKGROUND: Glutamine (Gln) plays a pivotal role in maintaining the integrity of the rumen epithelial barrier in mammals. This study aimed to investigate the effects of Gln on histamine-induced barrier damage in yak rumen epithelial cells (YRECs).
RESULTS: RT-qPCR analysis revealed a significant decrease in the mRNA expression of tight junction proteins (ZO-1, JAM-A, Claudin-1, and Claudin-4) following 24-hour exposure to 20 µM histamine (HIS group) (P < 0.05). In the subsequent experiment, YRECs were first treated with 20 µM histamine for 24 h, followed by 8 mM glutamine for 12 h (HG group). Gln treatment reversed the histamine-induced downregulation of both mRNA and protein levels of tight junction proteins and restored the distribution of ZO-1 at the cell membrane. Transcriptome analysis revealed that co-regulated differentially expressed genes were primarily involved in the mitogen-activated protein kinase (MAPK) signaling pathway and apoptosis. These findings were further corroborated by RT-qPCR, Western blot, and flow cytometry analyses. To determine whether glutamine regulates cell barrier function through the p38 MAPK signaling pathway, 20 µM Skatole, a p38 MAPK agonist, was introduced (SK group). The results showed a significant increase in the p-p38/p38 ratio and a marked decrease in the mRNA and protein expression of tight junction proteins in the SK group compared to the HG group (P < 0.05).
CONCLUSIONS: Glutamine mitigates histamine-induced barrier damage in YRECs through the p38 MAPK signaling pathway and apoptosis regulation.

Keywords:  Glutamine; Histamine; RNA-seq; Tight junction; Yak

DOI:  https://doi.org/10.1186/s12864-025-11383-6
HGG Adv. 2025 Feb 20. pii: S2666-2477(25)00022-3. [Epub ahead of print] 100419

Male proband with intractable seizures and a de novo start codon disrupting variant in GLUL.

Elizabeth Carbonell, Sarah L Stenton, Vijay S Ganesh, Jialan Ma, Grace E VanNoy, Lynn Pais, John N Gaitanis, Melanie C O'Leary, Heidi L Rehm, Anne O'Donnell-Luria.

Biallelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females all with a de novo single nucleotide variant within the start codon or the 5'UTR region of GLUL that truncate 17 amino acids of the protein product, including its critical N-terminal degron sequence, resulting in a disorder of abnormal glutamine synthetase stability and manifesting as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.

DOI: https://doi.org/10.1016/j.xhgg.2025.100419
Front Immunol. 2025 ;16 1508730

Targeting amino acid metabolism to inhibit gastric cancer progression and promote anti-tumor immunity: a review.

Yuchun Jiang, Qing Tao, Xuehan Qiao, Yufei Yang, Chen Peng, Miao Han, Kebin Dong, Wei Zhang, Min Xu, Deqiang Wang, Wen Zhu, Xiaoqin Li.

  The incidence of gastric cancer remains high and poses a serious threat to human health. Recent comprehensive investigations into amino acid metabolism and immune system components within the tumor microenvironment have elucidated the functional interactions between tumor cells, immune cells, and amino acid metabolism. This study reviews the characteristics of amino acid metabolism in gastric cancer, with a particular focus on the metabolism of methionine, cysteine, glutamic acid, serine, taurine, and other amino acids. It discusses the relationship between these metabolic processes, tumor development, and the body's anti-tumor immunity, and analyzes the importance of targeting amino acid metabolism in gastric cancer for chemotherapy and immunotherapy.

Keywords:  amino acid metabolism; chemotherapy resistance; immunotherapy; methylation; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1508730
Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb 28.

Plant-derived terpenoids modulating cancer cell metabolism and cross-linked signaling pathways: an updated reviews.

Pratibha Pandey, Meenakshi Verma, Gaurav Sanghvi, Roopashree R, Kamal Kant Joshi, Kavitha V, Subhashree Ray, Seema Ramniwas, Ajay Singh, Sorabh Lakhanpal, Fahad Khan.

  Cancer is a critical health issue that remains a predominant cause of mortality globally. It is a complex disease that may effectively regulate many signaling pathways and modify the metabolism of the body to evade the immune system. Understanding neoplastic metabolic reprogramming as a hallmark of cancer has facilitated the creation of innovative metabolism-targeted treatment strategies. Various signaling cascades, such as the PI3K/Akt/mTOR, ERK, JAK/STAT, MAPK/p38, NF-κB/Nrf2, and apoptotic pathways, are commonly involved in this process. It is now widely recognized that an inadequate response and the subsequent development of resistance are frequently caused by the highly selective blockage of these pathways in tumor cells. Consequently, to enhance the overall efficacy of anticancer agents, it is crucial to employ multi-target compounds that can concurrently inhibit multiple vital processes within tumor cells. The utilization of plant-derived bioactive compounds for this purpose is particularly promising, owing to their varied structures and numerous targets. Among these bioactive compounds, terpenoids have exhibited significant anticancer efficacy by targeting various altered signaling pathways. Thus, this review examines the terpenoid class of plant-derived compounds exhibiting potential anticancer activity, including their impact on metabolism and interconnected deregulated signaling pathways in human tumor cells. Accordingly, current research will help in the rational design and critical evaluation of innovative anticancer therapeutics utilizing plant-derived terpenoids for the modulation of cross-linked signaling pathways of cancer metabolism.

Keywords:  Anticancer; Cancer metabolism; Molecular targets; Plant-derived terpenoids; Signaling pathways

DOI:  https://doi.org/10.1007/s00210-025-03937-y
Antioxidants (Basel). 2025 Feb 10. pii: 197. [Epub ahead of print]14(2):

Divergent Requirements for Glutathione Biosynthesis During Osteoclast Differentiation In Vitro and In Vivo.

Guoli Hu, Amy L Whitaker, Guo-Fang Zhang, Courtney M Karner.

  Glutathione (GSH) is the most abundant antioxidant in the cell, and it is responsible for neutralizing reactive oxygen species (ROS). ROS can promote osteoclast differentiation and stimulate bone resorption and are some of the primary drivers of bone loss with aging and loss of sex steroids. Despite this, the role of GSH biosynthesis during osteoclastogenesis remains controversial. Here, we show that the requirements for GSH biosynthesis during osteoclastogenesis in vitro and in vivo are unique. Using a metabolomics approach, we discovered that both oxidative stress and GSH biosynthesis increase during osteoclastogenesis. Inhibiting GSH biosynthesis in vitro via the pharmacological or genetic inhibition of glutamate cysteine ligase (GCLC) prevented osteoclast differentiation. Conversely, the genetic ablation of GCLC in myeloid cells using LysMCre resulted in a decrease in bone mass in both male and female mice. The decreased bone mass of the LysMCre;Gclcfl/fl mice was attributed to increased osteoclast numbers and elevated bone resorption. Collectively, our data provide strong genetic evidence that GSH biosynthesis is essential for the regulation of osteoclast differentiation and bone resorption in mice. Moreover, these findings highlight the necessity of complementing in vitro studies with in vivo genetic studies.

Keywords:  bone; glutathione; osteoclast

DOI:  https://doi.org/10.3390/antiox14020197
Nature. 2025 Feb 26.

A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.

Hefei Zhang, Xuhang Li, L Tenzin Tseyang, Gabrielle E Giese, Hui Wang, Bo Yao, Jingyan Zhang, Rachel L Neve, Elizabeth A Shank, Jessica B Spinelli, L Safak Yilmaz, Albertha J M Walhout.

Metabolic flux, or the rate of metabolic reactions, is one of the most fundamental metrics describing the status of metabolism in living organisms. However, measuring fluxes across the entire metabolic network remains nearly impossible, especially in multicellular organisms. Computational methods based on flux balance analysis have been used with genome-scale metabolic network models to predict network-level flux wiring1-6. However, such approaches have limited power because of the lack of experimental constraints. Here, we introduce a strategy that infers whole-animal metabolic flux wiring from transcriptional phenotypes in the nematode Caenorhabditis elegans. Using a large-scale Worm Perturb-Seq (WPS) dataset for roughly 900 metabolic genes7, we show that the transcriptional response to metabolic gene perturbations can be integrated with the metabolic network model to infer a highly constrained, semi-quantitative flux distribution. We discover several features of adult C. elegans metabolism, including cyclic flux through the pentose phosphate pathway, lack of de novo purine synthesis flux and the primary use of amino acids and bacterial RNA as a tricarboxylic acid cycle carbon source, all of which we validate by stable isotope tracing. Our strategy for inferring metabolic wiring based on transcriptional phenotypes should be applicable to a variety of systems, including human cells.

DOI: https://doi.org/10.1038/s41586-025-08635-6
Front Immunol. 2025 ;16 1477437

A prognostic signature of Glutathione metabolism-associated long non-coding RNAs for lung adenocarcinoma with immune microenvironment insights.

Junxi Hu, Shuyu Tian, Qingwen Liu, Jiaqi Hou, Jun Wu, Xiaolin Wang, Yusheng Shu.

   Background: Glutathione (GSH) metabolism supports tumor redox balance and drug resistance, while long non-coding RNAs (lncRNAs) influence lung adenocarcinoma (LUAD) progression. This study developed a prognostic model using GSH-related lncRNAs to predict LUAD outcomes and assess tumor immunity.
Methods: This study analyzed survival data from The Cancer Genome Atlas (TCGA) and identified GSH metabolism-related lncRNAs using Pearson correlation. A prognostic model was built with Cox and Least Absolute Shrinkage and Selection Operator (LASSO) methods and validated by Kaplan-Meier analysis, Receiver Operating Characteristic (ROC) curves, and Principal Component Analysis (PCA). Functional analysis revealed immune infiltration and drug sensitivity differences. Quantitative PCR and experimental studies confirmed the role of lnc-AL162632.3 in LUAD.
Results: Our model included a total of nine lncRNAs, namely AL162632.3, AL360270.1, LINC00707, DEPDC1-AS1, GSEC, LINC01711, AL078590.2, AC026355.2, and AL096701.4. The model effectively forecasted patient survival, and the nomogram, incorporating additional clinical risk factors, satisfied clinical needs adequately. Patient stratification based on model scores revealed significant disparities in immune cell composition, functionality, and mutations between groups. Additionally, variations were noted in the IC50 values for key lung cancer medications such as Cisplatin, Docetaxel, and Paclitaxel. In vitro cell experiment results showed that AL162632.3 was markedly upregulated, while AC026355.2 tended to be downregulated across these cell lines. Ultimately, suppressing lnc-AL162632.3 markedly reduced the growth, mobility, and invasiveness of lung cancer cells.
Conclusion: This study identified GSH metabolism-related lncRNAs as key prognostic factors in LUAD and developed a model for risk stratification. High-risk patients showed increased tumor mutation burden (TMB) and stemness, emphasizing the potential of personalized immunotherapy to improve survival outcomes.

Keywords:  Glutathione metabolism; immune microenvironment; lncRNA; lung adenocarcinoma; prognostic prediction

DOI:  https://doi.org/10.3389/fimmu.2025.1477437
J Biol Chem. 2025 Feb 21. pii: S0021-9258(25)00187-5. [Epub ahead of print] 108338

Glutamate decarboxylase confers acid tolerance and enhances survival of mycobacteria within macrophages.

Rupal Rai, Bijina J Mathew, Rashmi Chourasia, Anirudh K Singh, Shivendra K Chaurasiya.

  Host-induced metabolic adaptations are crucial for Mycobacterium tuberculosis (Mtb) survival and drug resistance. Mtb's persistence in the acidic environments of phagosomes and phagolysosomes suggests its initial metabolic adjustments respond to acidic stress. Glutamate decarboxylase (Gad) enzyme, converts glutamate to GABA while consuming a proton, helping regulate intracellular pH in bacteria. However, the role of Gad in mycobacteria has been unexplored. In this study, we investigated the function of Gad in Mtb and Mycobacterium smegmatis (MS), which are encoded by Rv3432c (gadB) and MSMEG_1574 (gadA), an orthologue of gadB, respectively. We observed upregulation of gad in both Mtb and MS under acidic stress and during infection within macrophages. Additionally, the expression of genes involved in glutamate metabolism and the GABA shunt, such as glutamine synthetase (glnA1), glutamate dehydrogenase (gdh), glutamate synthase (gltD/B), GABA-aminotransferase (gab-T), succinic semialdehyde dehydrogenase (gabD1/gabD2), α-ketoglutarate dehydrogenase (kdh), and 2-oxoglutarate dehydrogenase (sucA), were responsive to acidic conditions, reflecting a metabolic shift. Similar gene expression patterns were observed during macrophage infection. These findings suggest that Gad plays a role in mycobacterial acid stress response. To further elucidate this, we generated an MS gadA knockout strain (MSΔgadA) using allelic exchange. MSΔgadA exhibited reduced survival at pH 3.0, a phenotype rescued by gene complementation. MSΔgadA also showed decreased survival within macrophages. Additionally, Mycobacterium bovis BCG, which lacks native Gad expression, demonstrated enhanced intracellular survival when overexpressing Mtb gadB. These results suggest that Gad confers acid tolerance and promotes intracellular survival in mycobacteria, highlighting its potential role in host adaptation.

Keywords:  Mycobacterium smegmatis; Mycobacterium tuberculosis; acid resistance; acid tolerance; bacterial metabolism; bacterial pathogenesis; glutamate decarboxylase; host‐pathogen interaction; phagocytosis; tuberculosis

DOI:  https://doi.org/10.1016/j.jbc.2025.108338
Pharmaceutics. 2025 Feb 12. pii: 244. [Epub ahead of print]17(2):

Recent Advances in Glutathione Depletion-Enhanced Porphyrin-Based nMOFs for Photodynamic Therapy.

Bin Gong, Qiuyun Zhang, Jiayi Chen, Yijie Qu, Xuanxuan Luo, Weiqi Wang, Xiaohua Zheng.

  Photodynamic therapy has established itself as a clinical treatment for certain superficial cancers by converting oxygen into cytotoxic singlet oxygen to eradicate cancer cells. Porphyrin-based nanoscale metal-organic frameworks have emerged as promising photosensitive platforms due to their ability to prevent the hydrophobic aggregation quenching of porphyrin molecules and enhance accumulation at the tumor site, thereby becoming a focal point in photodynamic materials research. However, the elevated levels of glutathione and other reductive substances within cancer cells can alleviate the oxidative stress induced by singlet oxygen from the photodynamic therapy process, thus protecting intracellular biomolecular structures from damage. Consequently, it is crucial to design functionalized nanoplatforms that integrate glutathione depletion with porphyrin-based metal-organic frameworks to significantly boost photodynamic therapy efficacy. Moreover, the excess glutathione within cells can disrupt the structure of porphyrin-based metal-organic frameworks, which not only increases the capacity of porphyrin molecules to generate singlet oxygen upon light exposure but also aids in the recovery of their fluorescence imaging capabilities. Additionally, this specificity minimizes the photosensitizing harm of porphyrin-based metal-organic frameworks to other normal tissues. This review compiles recent advancements in developing porphyrin-based metal-organic frameworks for enhanced phototherapy through glutathione depletion. It aims to promote the further application of porphyrin-based metal-organic frameworks in phototherapy and provide valuable insights for preclinical applications. By highlighting strategies that improve therapeutic outcomes while maintaining safety profiles, this summary seeks to advance the development of more effective and targeted cancer treatments.

Keywords:  glutathione depletion; metal–organic frameworks; photodynamic therapy; porphyrin; singlet oxygen

DOI:  https://doi.org/10.3390/pharmaceutics17020244
bioRxiv. 2025 Feb 16. pii: 2025.02.15.638423. [Epub ahead of print]

Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.

Fangtao Chi, Qiming Zhang, Jessica E S Shay, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Sumeet Solanki, Yatrik M Shah, Judith Agudo, Ömer H Yilmaz.

A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5 + intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5 + ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5 + ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5 + ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8αβ + T cells. These findings highlight how coupled cysteine metabolism between ISCs and CD8 + T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

DOI: https://doi.org/10.1101/2025.02.15.638423
Redox Biol. 2025 Feb 19. pii: S2213-2317(25)00073-4. [Epub ahead of print]81 103560

Characterization of the glutathione redox state in the Golgi apparatus.

Carla Miró-Vinyals, Sarah Emmert, Gina Grammbitter, Alex Jud, Tobias Kockmann, Pablo Rivera-Fuentes.

  Redox homeostasis is crucial for cell function, and, in eukaryotic cells, studying it in a compartmentalized way is essential due to the redox variations between different organelles. The redox state of organelles is largely determined by the redox potential of glutathione, EGSH, and the concentration of its reduced and oxidized species, [GS]. The Golgi apparatus is an essential component of the secretory pathway, yet little is known about the concentration or redox state of GSH in this organelle. Here, we characterized the redox state of GSH in the Golgi apparatus using a combination of microscopy and proteomics methods. Our results prove that the Golgi apparatus is a highly oxidizing organelle with a strikingly low GSH concentration (EGSH = - 157 mV, 1-5 mM). These results fill an important gap in our knowledge of redox homeostasis in subcellular organelles. Moreover, the new Golgi-targeted GSH sensors allow us to observe dynamic changes in the GSH redox state in the organelle and pave the way for further characterization of the Golgi redox state under various physiological and pathological conditions.

Keywords:  Glutathione; Golgi apparatus; Redox homeostasis; roGFP

DOI:  https://doi.org/10.1016/j.redox.2025.103560
Nature. 2025 Feb 26.

Systems-level design principles of metabolic rewiring in an animal.

Xuhang Li, Hefei Zhang, Thomas Hodder, Wen Wang, Chad L Myers, L Safak Yilmaz, Albertha J M Walhout.

The regulation of metabolism is vital to any organism and can be achieved by transcriptionally activating or repressing metabolic genes1-3. Although many examples of transcriptional metabolic rewiring have been reported4, a systems-level study of how metabolism is rewired in response to metabolic perturbations is lacking in any animal. Here we apply Worm Perturb-Seq (WPS)-a high-throughput method combining whole-animal RNA-interference and RNA-sequencing5-to around 900 metabolic genes in the nematode Caenorhabditis elegans. We derive a metabolic gene regulatory network (mGRN) in which 385 perturbations are connected to 9,414 genes by more than 110,000 interactions. The mGRN has a highly modular structure in which 22 perturbation clusters connect to 44 gene expression programs. The mGRN reveals different modes of transcriptional rewiring from simple reaction and pathway compensation to rerouting and more complex network coordination. Using metabolic network modelling, we identify a design principle of transcriptional rewiring that we name the compensation-repression (CR) model. The CR model explains most transcriptional responses in metabolic genes and reveals a high level of compensation and repression in five core metabolic functions related to energy and biomass. We provide preliminary evidence that the CR model may also explain transcriptional metabolic rewiring in human cells.

DOI: https://doi.org/10.1038/s41586-025-08636-5