bims-cesirm 2025-06-29 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–06–29
seventeen papers selected by
Tigist Tamir, University of North Carolina

Unraveling the role of GPCR signaling in metabolic reprogramming and immune microenvironment of lung adenocarcinoma: a multi-omics study with experimental validation.
Sodium-Glucose Cotransporter 2 and Glucose Levels Affect Clear Cell Renal Cell Carcinoma Progression.
ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer.
Decoding the NRF2-NOTCH Crosstalk in Lung Cancer-An Update.
Sirtuin 5 inhibits mitochondrial metabolism in liver cancer cells and promotes apoptosis by mediating the desuccinylation of CS.
Nutrition and Diet Patterns as Key Modulators of Metabolic Reprogramming in Melanoma Immunotherapy.
Landscape of metabolic alterations and treatment strategies in breast cancer.
Baicalein suppresses the malignant progression of acute myeloid leukemia via ROS-dependent metabolic reprogramming: Mechanisms of differentiation induction and ferroptosis activation.
Unravelling the Adiponectin Hallmark and Exploring the Therapeutic Potential of Its Receptor Agonists in Cancer Metabolic Reprogramming.
Integrated Single-Tip IMAC-HILIC Enables Simultaneous Analysis of Plant Phosphoproteomics and N-Glycoproteomics.
Dimethyl malonate alleviates obstructive nephropathy by enhancing renal metabolism and inhibiting kidney oxidative stress and inflammation.
The metabolic shift of glutaminase 2 to glutaminase 1 promotes LGR5 + progenitor cell proliferation in liver cirrhosis.
Genome-scale knockout simulation and clustering analysis of drug-resistant breast cancer cells reveal drug sensitization targets.
How Do Cancer Cells Create Cancer-Associated Fibroblast Subtypes? Impacts of Extracellular Vesicles on Stromal Diversity.
Serum Extracellular Vesicles Reveal Metabolic Responses to Time-Restricted Feeding in High-Fat Diet-Induced Obesity in Male Mice.
Targeting lipid metabolism to overcome tamoxifen resistance in breast cancer: Evaluating the synergistic therapeutic potential of quercetin.
TYROBP overexpression alters macrophage phenotype and enhances pancreatic cancer stemness through STAT3 and PKM2 signaling.

Front Immunol. 2025 ;16 1606125

Unraveling the role of GPCR signaling in metabolic reprogramming and immune microenvironment of lung adenocarcinoma: a multi-omics study with experimental validation.

Zhaoxuan Wang, Cheng Wang, Shilei Zhao, Chundong Gu.

   Background: Lung adenocarcinoma (LUAD) is characterized by metabolic and immune heterogeneity, driving tumor progression and therapy resistance. While G protein-coupled receptors (GPCR) signaling is known to regulate metabolism and immunity in cancers, its role in LUAD remains poorly defined. This study explores the influence of GPCR signaling on LUAD metabolism and immune landscape.
Methods: We performed non-negative matrix factorization (NMF) clustering of GPCR signaling genes in TCGA-LUAD cohort to identify distinct molecular subgroups. A prognostic model was developed based on GPCR signaling genes using least absolute shrinkage and selection operator (LASSO) analysis and Cox regression. Differentially expressed genes were analyzed for metabolic pathway enrichment and immune infiltration. In addition, key genes within GPCR signaling were identified and validated through functional assays.
Results: NMF clustering based on GPCR signaling identified three subgroups in LUAD, with cluster 3 exhibiting poorer overall survival and significant enrichment in multiple prognostic associated metabolism pathways including purine, pyrimidine, glyoxylate and dicarboxylate metabolism. Then, we developed a GPCRscore prognostic model and validated across multiple cohorts, which effectively stratified LUAD patients into distinct risk groups. High-risk LUAD patients had an immunosuppressive microenvironment and activated metabolic reprogramming. ADM was identified as a key gene in the high-risk group, correlating with tumor stage, immune suppression, and resistance to immunotherapy. Clinically, ADM was highly expressed in tumor tissues and shows elevated concentrations in the peripheral blood of patients with advanced-stage LUAD. Subsequently, we demonstrated that knock-down of ADM in LUAD cells impaired their proliferation, migration, and invasion, while also reducing the angiogenic potential of endothelial cells in vitro. Adrenomedullin promoted LUAD progression in a murine metastasis model. Further, adrenomedullin inhibited CD8+ T cells proliferation, induced exhaustion, and impaired cytotoxic function. Finally, drug sensitivity and cell viability analysis showed LUAD patients with high levels of ADM exhibited sensitivity to the treatment of Staurosporine and Dasatinib.
Conclusions: In summary, this study reveals the pivotal role of GPCR signaling particularly mediated by ADM in orchestrating metabolic reprogramming and immune modulation in LUAD. ADM emerges as a potential predictive biomarker and therapeutic target, offering valuable implications for optimizing strategies.

Keywords:  ADM; GPCR signaling; immune microenvironment; lung adenocarcinoma; metabolic reprogramming; prognostic model

DOI:  https://doi.org/10.3389/fimmu.2025.1606125
Int J Mol Sci. 2025 Jun 08. pii: 5501. [Epub ahead of print]26(12):

Sodium-Glucose Cotransporter 2 and Glucose Levels Affect Clear Cell Renal Cell Carcinoma Progression.

Yujiro Nagata, Ikko Tomisaki, Hisami Aono, Nguyen Thu Quynh, Eiji Kashiwagi, Naohiro Fujimoto.

  The biological significance of sodium-glucose cotransporter 2 (SGLT2) in clear cell renal cell carcinoma (ccRCC) has yet to be elucidated. In this study, we aimed to determine the role of SGLT2 in ccRCC tumor progression. The human ccRCC line KMRC-1, which contains a von Hippel-Lindau (VHL) gene mutation, was used to assess the effects of the SGLT2 inhibitor (SGLT2i) dapagliflozin on proliferation and migration in media containing different glucose concentrations (25, 12.5, or 5 mM). Dapagliflozin significantly reduced cell proliferation and migration in 25 mM glucose medium. Similarly, SGLT2 knockdown involving short hairpin RNA lentiviral transfection significantly decreased cell viability, migration, and colony formation compared with the control subline in 25 mM glucose medium. Moreover, tumor progression was inhibited in the media with low glucose concentrations. Remarkably, 2 µM dapagliflozin inhibited the progression of ccRCC at concentrations as low as 5 mM (normoglycemic model) glucose medium as well as 25 mM (severe glycemia model) glucose medium. In addition, dapagliflozin treatment significantly enhanced the apoptosis of ccRCC cells. Our findings demonstrate that SGLT2 impacts the progression of ccRCC with the VHL mutation. In light of the above findings, SGLT2is, which exert the dual effects of SGLT2 blockade and glycemic control, may represent a novel therapeutic agent, particularly in patients with ccRCC who suffer from concurrent diabetes mellitus. To the best of our knowledge, this is the first preclinical study demonstrating the impact of SGLT2 inhibition on the progression of ccRCC with the VHL mutation.

Keywords:  SGLT2; clear cell renal cell carcinoma; glucose; tumor progression; von Hippel–Lindau gene

DOI:  https://doi.org/10.3390/ijms26125501
Oncogene. 2025 Jun 27.

ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer.

Hui Liu, Zhifeng Zhao, Changle Wu, Jinxin Chen, Zhiwei He, Kai Jiang.

Pancreatic cancer (PC) is a digestive tract tumour with an extremely poor patient prognosis and prominent metabolic abnormalities. However, the molecular mechanisms underlying metabolic reprogramming in the progression of pancreatic cancer remain poorly understood. Here, we employed an epigenetic siRNA library to identify a crucial regulator, ZMYND8, which is involved in glycolysis in PC cells. ZMYND8 was frequently overexpressed in both PC tissues and cell lines, and its elevated expression was significantly correlated with poor overall survival in patients with PC. The high rates of glucose uptake and lactate secretion conferred by ZMYND8 revealed an abnormal activity of aerobic glycolysis in PC cells. Functional studies revealed that ZMYND8 significantly promoted the proliferation, migration and invasion of PC cells. Integrated analyses of CUT&Tag and RNA-seq data revealed that ZMYND8 may activate c-Myc transcriptional activity by modulating downstream epigenetic regulatory pathways. Proteomic profiling and coimmunoprecipitation (Co-IP) assays further demonstrated a direct physical interaction between ZMYND8 and c-Myc. Mechanistic studies revealed that ZMYND8 interacted with and activated c-Myc, thereby promoting the Warburg effect and facilitating PC cell malignancy. Moreover, in vivo studies revealed that overexpression of ZMYND8 resulted in accelerated tumour growth in PC xenografts, which was reversible through the knockdown of c-Myc or treatment with 2-deoxy-D-glucose. Collectively, our data suggest that ZMYND8 functions as a critical metabolic regulator in PC cells by tightly regulating c-Myc activity and may represent a promising novel therapeutic target for advanced pancreatic cancer treatment.

DOI: https://doi.org/10.1038/s41388-025-03483-0
Antioxidants (Basel). 2025 May 29. pii: 657. [Epub ahead of print]14(6):

Decoding the NRF2-NOTCH Crosstalk in Lung Cancer-An Update.

Angelo Sparaneo, Filippo Torrisi, Floriana D'Angeli, Giovanni Giurdanella, Sara Bravaccini, Lucia Anna Muscarella, Federico Pio Fabrizio.

  The Nuclear factor erythroid 2-related factor 2 (NRF2) Neurogenic locus NOTCH homolog protein (NOTCH) crosstalk has emerged as a critical regulatory axis in the progression of solid cancers, especially lung, affecting tumor growth and resistance to therapy. NRF2 is a master transcription factor that orchestrates the cellular antioxidant response, while NOTCH signaling is involved in the cell-cell communication processes by influencing the patterns of gene expression and differentiation. Although frequently altered independently, genetic and epigenetic dysregulation of both NRF2 and NOTCH pathways often converge to deregulate oxidative stress responses and promote tumor cell survival. Recent findings reveal that the NRF2/NOTCH interplay extends beyond canonical signaling, contributing to metabolic reprogramming and reshaping the tumor microenvironment (TME) to promote cancer malignancy. Emerging scientific evidences highlight the key role of biochemical and metabolomic changes within NRF2-NOTCH crosstalk, in contributing to cancer progression and metabolic reprogramming, beyond facilitating the adaptation of cancer cells to the TME. Actually, the effects of the NRF2-NOTCH bidirectional interaction in either supporting or suppressing lung tumor phenotypes are still unclear. This review explores the molecular mechanisms underlying NRF2-NOTCH crosstalk in lung cancer, highlighting the impact of genetic and epigenetic deregulation mechanisms on neoplastic processes, modulating the TME and driving the metabolic reprogramming. Furthermore, we discuss therapeutic opportunities for targeting this regulatory network, which may open new avenues for overcoming drug resistance and improving clinical outcomes in lung cancer.

Keywords:  NOTCH; NRF2; lung cancer; oxidative stress; resistance

DOI:  https://doi.org/10.3390/antiox14060657
Front Immunol. 2025 ;16 1560989

Sirtuin 5 inhibits mitochondrial metabolism in liver cancer cells and promotes apoptosis by mediating the desuccinylation of CS.

Huimin Cao, Dongsheng Wei, Han Li, Mei Zhao, Yixin Ma, Liang Kong, Guoyuan Sui, Lianqun Jia.

   Background: Citrate synthase (CS) is a key rate-limiting enzyme in the tricarboxylic acid (TCA) cycle and plays a crucial role in cancer progression. However, the mechanism by which CS promotes liver cancer growth remains unclear. The aim of this study is to elucidate the role of CS and its post-translational modifications (PTMs) in the initiation and progression of hepatocellular carcinoma (HCC).
Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect protein lysine succinylation in human liver cancer and adjacent non-cancerous tissues. A HCC model was established in male C57BL/6 mice through intraperitoneal injection of DEN. The expression of SIRT5 and CS in HCC mice was assessed by RT-qPCR, immunohistochemistry, and Western blotting. HepG2 cells were cultured, and co-immunoprecipitation (Co-IP) was performed to evaluate the interaction between SIRT5 and CS. Western blotting was used to measure the succinylation levels of CS. In addition, Mito-Tracker Red CMXRos staining, reactive oxygen species (ROS) measurement, ATP level assay, EdU cell proliferation assay, colony formation assay, TUNEL staining, and flow cytometry were used to investigate the effects of CS succinylation and desuccinylation on mitochondrial function and cell proliferation in hepatocellular carcinoma cells.
Results: A total of 358 differentially modified proteins were identified in human liver cancer tissues. These differentially modified proteins were primarily enriched in the mitochondria, and CS exhibited high levels of succinylation in HCC tissues. In mouse liver cancer tissues, SIRT5 expression was reduced while CS expression was increased. Furthermore, SIRT5 was found to interact with CS, mediating the de-succinylation of CS at the lysine 375 site. Additionally, succinylation at the K375 site of CS was shown to enhance mitochondrial activity and ATP content in HepG2 cells, while reducing intracellular ROS levels and promoting cell proliferation. In contrast, de-succinylation of CS at the K375 site significantly impaired mitochondrial function and ATP levels, increased ROS levels, and induced apoptosis in HepG2 cells.
Conclusion: Succinylation of CS is crucial for maintaining mitochondrial function and promoting cell proliferation in liver cancer cells. Targeting SIRT5-mediated de-succinylation of CS may represent a promising therapeutic strategy for the treatment of hepatocellular carcinoma.

Keywords:  PTMs (post-translational modifications); apoptosis; citrate synthase; hepatocellular carcinoma; mitochondrial metabolism; succinylation

DOI:  https://doi.org/10.3389/fimmu.2025.1560989
J Clin Med. 2025 Jun 12. pii: 4193. [Epub ahead of print]14(12):

Nutrition and Diet Patterns as Key Modulators of Metabolic Reprogramming in Melanoma Immunotherapy.

Katerina Grafanaki, Alexandros Maniatis, Alexandra Anastogianni, Angelina Bania, Efstathia Pasmatzi, Constantinos Stathopoulos.

  Background: Melanoma, one of the most aggressive forms of skin cancer, has seen significant therapeutic advances with immune checkpoint inhibitors (ICIs). However, many patients fail to respond or develop resistance, creating the need for adjunct strategies. Objective: The objective of this study is to critically evaluate how specific dietary patterns and nutrient-derived metabolites modulate melanoma metabolism and immunotherapy outcomes, emphasizing translational implications. Methods: We performed an integrative review of preclinical and clinical studies investigating dietary interventions in melanoma models and ICI-treated patients. Mechanistic insights were extracted from studies on nutrient transport, immunometabolism, and microbiome-immune interactions, including data from ongoing nutritional clinical trials. Results: Diets rich in fermentable fibers, plant polyphenols, and unsaturated lipids, such as Mediterranean and ketogenic diets, seem to contribute to the reprogramming of tumor metabolism and enhance CD8+ T-cell activity. Fasting-mimicking and methionine-restricted diets modulate T-cell fitness and tumor vulnerability via nutrient stress sensors (e.g., UPR, mTOR). High fiber intake correlates with favorable gut microbiota and improved ICI efficacy, while excess protein, methionine, or refined carbohydrates impair immune surveillance via lactate accumulation and immunosuppressive myeloid recruitment. Several dietary molecules act as network-level modulators of host and microbial proteins, with parallels to known drug scaffolds. Conclusions: Integrating dietary interventions into melanoma immunotherapy can significantly influence metabolic reprogramming by targeting metabolic vulnerabilities and reshaping the tumor-immune-microbiome axis. When combined with AI-driven nutrient-protein interaction mapping, this approach offers a precision nutrition paradigm that supports both physicians and patients, emerging as a novel layer to enhance and consolidate existing therapeutic strategies.

Keywords:  immunotherapy; melanoma; metabolism; nutrition

DOI:  https://doi.org/10.3390/jcm14124193
Genes Dis. 2025 Sep;12(5): 101521

Landscape of metabolic alterations and treatment strategies in breast cancer.

Xiujuan Wu, Xuanni Tan, Yangqiu Bao, Wenting Yan, Yi Zhang.

  Breast cancer, the most prevalent cancer in women, poses a significant threat to their health. One of the prominent characteristics of malignant transformation in breast cancer cells is metabolic reprogramming, which encompasses glucose, lipid, and amino acid metabolism. Notably, breast cancer cells exhibit augmented energy metabolism and heightened glycolysis. In addition, there is an escalated demand for glutamine, which is met through intrinsic synthesis, uptake from extracellular sources via membrane transport proteins, or up-regulation of key metabolic enzymes in the glutamine metabolism pathway. Lipids not only serve as an energy source for tumor cells but also function as signaling molecules for intercellular communication. Extensive research in recent years has focused on unraveling the intricate mechanisms underlying metabolic reprogramming. Consequently, genes implicated in these processes have emerged as clinical therapeutic targets for cancer treatment. This review provides a comprehensive summary of the common metabolic alterations observed in cancer cells, discusses the factors and regulatory mechanisms influencing these changes, and explores potential therapeutic targets and strategies within the realm of cancer metabolism.

Keywords:  Amino acid metabolism; Breast cancer; Glucose metabolism; Lipid metabolism; Metabolic alterations

DOI:  https://doi.org/10.1016/j.gendis.2025.101521
Eur J Pharmacol. 2025 Jun 19. pii: S0014-2999(25)00593-X. [Epub ahead of print]1002 177839

Baicalein suppresses the malignant progression of acute myeloid leukemia via ROS-dependent metabolic reprogramming: Mechanisms of differentiation induction and ferroptosis activation.

Meishi Wang, Yuhan Wang, Ling Chen, Shuangle Yu, Xiaodan Li, Gang Huang, Mingming Jin.

  Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy driven by metabolic reprogramming, including dysregulated aerobic glycolysis and reactive oxygen species (ROS) signaling, which promote disease progression and therapeutic resistance. Although baicalein (BC) has demonstrated anti-tumor potential in various cancers, its specific role and molecular mechanisms in AML remain unclear. This study aimed to elucidate the effects and regulatory mechanisms of BC in AML. Network pharmacology analysis predicted BC's involvement in ROS regulation, myeloid differentiation, metabolic processes, and ferroptosis. In vitro experiments revealed that BC inhibited HL-60 cell proliferation and induced G0/G1 cell cycle arrest. Low concentrations of BC promoted ROS accumulation and myeloid differentiation, as evidenced by elevated CD11b and CD14 levels, which were reversed by ROS inhibitors. High concentrations of BC triggered ferroptosis via the SLC7A11/GSH/GPX4 pathway, confirmed by molecular docking and SLC7A11 overexpression. BC also suppressed aerobic glycolysis at both low and high concentrations. In vivo, BC significantly inhibited tumor progression in an HL-60 xenograft model by suppressing aerobic glycolysis. These findings demonstrate that BC modulates AML progression through concentration-dependent ROS accumulation, inducing differentiation at low doses and ferroptosis at high doses, offering a novel strategy for targeting the metabolism-oxidative stress axis in AML therapy.

Keywords:  Acute myeloid leukemia; Aerobic glycolysis; Baicalein; Differentiation; Ferroptosis; SLC7A11

DOI:  https://doi.org/10.1016/j.ejphar.2025.177839
Biomolecules. 2025 Jun 05. pii: 820. [Epub ahead of print]15(6):

Unravelling the Adiponectin Hallmark and Exploring the Therapeutic Potential of Its Receptor Agonists in Cancer Metabolic Reprogramming.

Sanober Kafeel, Giuseppina Palmiero, Alessia Salzillo, Angela Ragone, Silvio Naviglio, Luigi Sapio.

  As the most abundant fat-derived hormone, adiponectin plays an essential role in regulating energy homeostasis. Current evidence proposes the serum levels of adiponectin as a risk factor and a diagnostic/prognostic biomarker in cancer. Moreover, distinctive antineoplastic features have also been reported as a result of adiponectin supplementation in preclinical models. Mapping of the cancer-associated metabolic changes has elucidated a highly adaptable and interconnected system that allows malignant cells to sustain their growth and survival. Along with the pyruvate into acetyl-CoA conversion, downregulation of both lactate dehydrogenase and glycolysis-related genes depicts the main adiponectin-induced perturbations affecting glucose metabolism in cancer. Meanwhile, a multi-level approach involving lipid trafficking, catabolism, and de novo synthesis has been attributed to adiponectin in malignancies. The adiponectin receptor agonist AdipoRon has recently been recognized as a promising antineoplastic compound. Remarkably, AdipoRon-mediated changes in cancer metabolism occur together with its antiproliferative potential. This review aimed at recapitulating the modulatory effects of adiponectin, as well as those of its synthetic receptor agonists, in driving metabolic alterations in cancerous cells. A critical discussion is also conducted to deduce whether the adiponectin axis could serve as a putative target to address the metabolic reprogramming in cancer progression.

Keywords:  AdipoRon; adiponectin; cancer; metabolism

DOI:  https://doi.org/10.3390/biom15060820
J Proteome Res. 2025 Jun 23.

Integrated Single-Tip IMAC-HILIC Enables Simultaneous Analysis of Plant Phosphoproteomics and N-Glycoproteomics.

Chin-Wen Chen, Ting-An Chen, Pei-Yi Lin, Shu-Yu Lin, Chuan-Chih Hsu.

  Protein phosphorylation and N-glycosylation are key post-translational modifications (PTMs) in plants that regulate critical signaling processes. However, coanalysis of these PTMs is often complicated by their relatively low abundance and divergent enrichment requirements. Here, we present a single-tip IMAC-HILIC approach that integrates immobilized metal affinity chromatography (IMAC) and hydrophilic interaction chromatography (HILIC) materials within one pipet tip, enabling concurrent enrichment and sequential elution of phosphopeptides and N-glycopeptides. This integrated workflow effectively reduces phosphopeptide coelution during N-glycopeptide elution and streamlines sample processing. In direct comparison with the tandem-tip TIMAHAC method, our single-tip strategy achieves a comparable identification depth and offers superior quantitative accuracy for N-glycopeptides. We further demonstrate its applicability by examining the impact of calcium deprivation in Arabidopsis, revealing distinct global changes in both the phosphoproteome and N-glycoproteome. Our optimized protocol thus provides a straightforward and high-throughput platform for dual PTM profiling in complex plant samples, paving the way for broader investigations of PTM crosstalk in diverse physiological and stress responses.

Keywords:  N-glycoproteomics; enrichment; hydrophilic interaction Chromatography; immobilized metal affinity chromatography; phosphoproteomics

DOI:  https://doi.org/10.1021/acs.jproteome.5c00185
Front Pharmacol. 2025 ;16 1530635

Dimethyl malonate alleviates obstructive nephropathy by enhancing renal metabolism and inhibiting kidney oxidative stress and inflammation.

Wei Zhang, Changde Fu, Jinjin Lai, Jun Xin, Wenbin Zhang.

   Introduction: Obstructive nephropathy is a leading cause of renal injury and fibrosis. Mitochondrial dysfunction represents a hallmark of obstructive nephropathy, a condition that leads to metabolic aberrations, succinate accumulation, reactive oxygen species (ROS) overproduction, tubular damage, and kidney inflammation. Succinate dehydrogenase (SDH) is central to mitochondrial metabolism and targeting SDH with dimethyl malonate (DMM) has been shown to be effective in treating renal ischemia-reperfusion (IR) injury in the murine model. However, the therapeutic potential and underlying mechanisms of DMM against obstructive nephropathy have not been investigated.
Methods: We utilized the unilateral ureteral obstruction (UUO) mouse model to investigate the therapeutic potential of DMM in obstructive nephropathy. Histology, renal fibrosis, and inflammation were analyzed. A murine tubular cell line was used to investigate molecular mechanisms.
Results: DMM administration mitigated UUO-induced renal fibrosis. Transcriptome analysis revealed that DMM promoted mitochondrial function and inhibited renal inflammation in UUO kidneys. The upregulated genes in DMM-treated mice were enriched in metabolic pathways related to fatty acids, organic acids, amino acids, and the PPAR signaling. DMM suppressed the accumulation of CD4+ T cells and the production of inflammatory cytokines in UUO kidneys. Moreover, DMM reduced oxidative stress by decreasing mitochondrial ROS production in tubular cells. Mechanistically, at least in part, DMM activated the PPAR signaling pathway in tubular cells, thereby enhancing fatty acid oxidation (FAO) activity and mitochondrial function. Pharmacological activation of PPAR protected against UUO-induced kidney fibrosis and inflammation.
Conclusion: Our study suggests that targeting SDH with DMM could be a promising therapeutic strategy for obstructive nephropathy.

Keywords:  dimethyl malonate; inflammation; mitochondria; obstructive nephropathy; oxidative stress

DOI:  https://doi.org/10.3389/fphar.2025.1530635
Cell Mol Life Sci. 2025 Jun 23. 82(1): 251

The metabolic shift of glutaminase 2 to glutaminase 1 promotes LGR5 + progenitor cell proliferation in liver cirrhosis.

Defu Kong, Qi Zhou, Kang He, Janette Heegsma, Hans Blokzijl, Vincent E de Meijer, Klaas Nico Faber.

   BACKGROUND AND AIM: Liver regeneration is impaired in end-stage liver disease characterized by advanced fibrosis and cirrhosis, where metabolic reprogramming is considered as a therapeutic target. The shift in glutaminolysis from liver-type Glutaminase 2 (GLS2) to kidney-type Glutaminase 1 (GLS1) is crucial in different liver diseases, though its role in liver progenitor cell-mediated regeneration remains unclear. This study aimed to analyze the expression of glutamine-metabolizing enzymes in fibrotic human livers and investigate the role of GLS1 in LGR5+-progenitor cell expansion in liver regeneration.
METHODS: Healthy and chronically diseased human liver tissue from patients with alcoholic liver disease, viral hepatitis, biliary atresia, primary biliary cholangitis or non-alcoholic steatohepatitis were immunostained for GLS1, GLS2 and glutamine synthetase (GS), and co-stained for LGR5. GLS1 was inhibited in adult progenitor cell-rived human liver organoids to evaluate its role in stemness and cell proliferation pathways.
RESULTS: GLS1 expression was enhanced and GLS2 decreased in chronic liver diseases compared to healthy liver. GLS1 was expressed in parenchymal, including hepatocytes, and non-parenchymal cells. In cirrhotic livers, GLS1+ hepatocytes showed a spatial distribution comparable to the progenitor cell marker LGR5. The GLS1 inhibitor CB839 suppressed progenitor cell markers (LGR5 and AXIN2) via the ROS-Wnt/β-Catenin pathway, which was rescued by glutathione (GSH). The CB839-mediated decrease in cell proliferation in human liver organoids was rescued by non-essential amino acids.
CONCLUSIONS: This study identifies GLS1 as a metabolic regulator of progenitor cell expansion aiding liver regeneration in various etiologies of human liver cirrhosis.

Keywords:  GSH; Glutaminase 1; Glutamine metabolism; Liver fibrosis; Liver organoids; Proliferation

DOI:  https://doi.org/10.1007/s00018-025-05772-z
Proc Natl Acad Sci U S A. 2025 Jul;122(26): e2425384122

Genome-scale knockout simulation and clustering analysis of drug-resistant breast cancer cells reveal drug sensitization targets.

JinA Lim, Hae Deok Jung, Soo Young Park, Moonhyeon Jeon, Da Sol Kim, Ryeongeun Cho, Dohyun Han, Han Suk Ryu, Yoosik Kim, Hyun Uk Kim.

  Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance remains a major hurdle. Metabolic reprogramming is a notable phenotype associated with the acquisition of drug resistance. Here, we develop a computational framework that predicts metabolic gene targets capable of reverting the metabolic state of drug-resistant cells to that of drug-sensitive parental cells, thereby sensitizing the resistant cells. The computational framework performs single-gene knockout simulation of genome-scale metabolic models that predicts genome-wide metabolic flux distribution in drug-resistant cells, and clusters the resulting knockout flux data using uniform manifold approximation and projection, followed by k-means clustering. From the clustering analysis, knockout genes that lead to the flux data near that of drug-sensitive cells are considered drug sensitization targets. This computational approach is demonstrated using doxorubicin- and paclitaxel-resistant MCF7 breast cancer cells. Drug sensitization targets are further refined based on proteome and metabolome data, which generate GOT1 for doxorubicin-resistant MCF7, GPI for paclitaxel-resistant MCF7, and SLC1A5 as a common target. These targets are experimentally validated where treating drug-resistant cancer cells with small-molecule inhibitors results in increased sensitivity of drug-resistant cells to doxorubicin or paclitaxel. The applicability of the developed framework is further demonstrated using drug-resistant triple-negative breast cancer cells. Taken together, the computational framework predicts drug sensitization targets in an intuitive and cost-efficient manner and can be applied to overcome drug-resistant cells associated with various cancers and other metabolic diseases.

Keywords:  anticancer drug resistance; drug sensitization; genome-scale metabolic model; metabolic reprogramming; single-gene knockout simulation

DOI:  https://doi.org/10.1073/pnas.2425384122
Cancer Sci. 2025 Jun 25.

How Do Cancer Cells Create Cancer-Associated Fibroblast Subtypes? Impacts of Extracellular Vesicles on Stromal Diversity.

Yutaka Naito.

  Cancer-associated fibroblasts (CAFs) are the major component of the tumor stroma. They mediate various attributes of tumor cells, such as cell growth, migration, invasion, angiogenesis, metabolic reprogramming, apoptosis, immune regulation, and extracellular matrix reconstitution, all related to cancer progression and treatment resistance. Although many researchers have recognized CAF heterogeneity, recent technological advances have emphasized the functional and phenotypic diversity of CAFs in cancer progression. Why are these CAF subtypes generated within tumor tissues? And how do cancer cells dictate such heterogeneous subtypes of CAFs? This review will highlight the CAF subtypes within the tumor microenvironment and their role in tumor progression. CAF subtype induction by extracellular vesicles (EVs) and their significance, which we reported previously, is also discussed.

Keywords:  cancer‐associated fibroblasts; extracellular vesicles; heterogeneity; subtypes; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.70133
J Extracell Biol. 2025 Jun;4(6): e70062

Serum Extracellular Vesicles Reveal Metabolic Responses to Time-Restricted Feeding in High-Fat Diet-Induced Obesity in Male Mice.

Theresa Bushman, Te-Yueh Lin, Xuenan Jin, Qin Fu, Sheng Zhang, Xiaoli Chen.

  Extracellular vesicle (EV) secretion and cargo composition are dysregulated in metabolic diseases. This study aimed to investigate how changes in serum EV concentration and protein composition reflect the metabolic effects of a high-fat diet (HFD) and time-restricted feeding (TRF), with a particular focus on adipocyte-derived EVs (Ad-EVs) in circulation. Mice were fed an HFD for 18 weeks prior to being placed either ad libitum or on a TRF for an additional 10 weeks. Mice on a normal chow ad libitum served as the control. The TRF group had food available for 10 h and fasted for 14 h per day. The serum EV size profile and amount displayed sex- and age-dependent changes in HFD-induced obesity, with age reducing EV amounts. HFD decreased small EV populations and increased larger EV populations, while TRF reversed these changes. Quantitative proteomic analysis showed that the abundance and composition of EV proteins changed in response to both acute stimulation with lipopolysaccharides (LPS) and HFD. Gene ontology analysis identified specific sets of EV proteins and their involved biological processes, reflecting the effect of LPS and HFD, as well as the reversal effect of TRF on metabolic and inflammatory pathways. EV proteins altered by HFD and those reversed by TRF had low protein overlap but significant functional overlap in biological processes. TRF activated the PPAR signalling pathway and the AKT-mTOR signalling pathway. The most significant impacts of HFD and TRF were observed on lipoprotein and carbohydrate metabolism, the complement system, and neutrophil degranulation. Additionally, we showed that serum Ad-EVs respond dynamically to HFD and TRF. Our findings suggest that EVs play a role in diet-induced metabolic and inflammatory responses, with changes in circulating EVs, particularly Ad-EVs, reflecting metabolic adaptations to dietary exposures and interventions.

Keywords:  extracellular vesicles; inflammation; obesity; proteomics; time‐restricted feeding

DOI:  https://doi.org/10.1002/jex2.70062
Cancer Treat Res Commun. 2025 Jun 10. pii: S2468-2942(25)00089-9. [Epub ahead of print]44 100953

Targeting lipid metabolism to overcome tamoxifen resistance in breast cancer: Evaluating the synergistic therapeutic potential of quercetin.

Radwa M Rifaat, Marwa W Kamel, Marwa Sharaky, Yasmin M Attia, Samia A Shouman.

  Breast cancer remains the most prevalent malignancy among women globally, with hormone receptor-positive subtypes representing the majority of cases. Despite significant advances in treatment, resistance to Tamoxifen, a cornerstone therapy for estrogen receptor-positive (ER+) breast cancer, poses a critical challenge, affecting up to 50 % of patients. Emerging evidence suggests that dysregulated lipid metabolism plays a pivotal role in breast cancer progression and therapy resistance. This systematic review aims to explore the intricate relationship between lipid metabolism and Tamoxifen resistance, with a particular focus on the potential therapeutic synergy of combining Tamoxifen with lipid metabolism modulators, such as Quercetin. We systematically searched PubMed, Scopus, Web of Science, and the Cochrane Library for studies published between 2000 and 2023, examining the role of lipid metabolic pathways in breast cancer and the impact of Quercetin on enhancing Tamoxifen efficacy. The findings suggest that targeting key enzymes involved in lipid metabolism, including fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC), may impair cancer cell survival mechanisms and sensitize tumors to Tamoxifen. The combination of Tamoxifen and Quercetin appears to exhibit synergistic effects, enhancing apoptosis and reducing cell proliferation more effectively than either agent alone. This review highlights the potential of combining Tamoxifen with Quercetin as a therapeutic strategy to overcome Tamoxifen resistance, providing a rationale for further clinical trials to investigate this combination therapy.

Keywords:  Acetyl-CoA Carboxylase (ACC); Breast cancer; Fatty acid synthase (FASN); Lipid metabolism; Quercetin; Tamoxifen resistance

DOI:  https://doi.org/10.1016/j.ctarc.2025.100953
Cell Signal. 2025 Jun 17. pii: S0898-6568(25)00364-X. [Epub ahead of print] 111949

TYROBP overexpression alters macrophage phenotype and enhances pancreatic cancer stemness through STAT3 and PKM2 signaling.

Dingwen Zhong, Yonghui Liao, Wenhui Chen, Xianyu Huang, Jiaxin Liu, Xinsong Fu, Zheng Wang.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME) that influences tumor progression and therapeutic responses. TYRO protein tyrosine kinase binding protein (TYROBP), a transmembrane polypeptide involved in immune cell signaling, has been implicated in PDAC and associated with M2 macrophage polarization.
METHODS: We investigated the correlation between TYROBP expression and M2 macrophage infiltration in PDAC tissues using multiplex immunofluorescence staining. We also engineered TYROBP overexpression in SW1990 and Capan-1 pancreatic cancer cell lines to evaluate its impact on cell migration and macrophage polarization. Furthermore, we conducted co-culture experiments with SW1990 cells and THP-1 cells to explore the role of TYROBP in macrophage-mediated SW1990 cell proliferation and stemness. Nuclear translocation of STAT3 and PKM2 was assessed in TYROBP-overexpressing SW1990 cells, and the regulatory effects of STAT3 and PKM2 on CXCL8 expression were examined. Finally, molecular docking studies were performed to evaluate the binding of baicalein to STAT3, and in vivo studies assessed the inhibitory effects of baicalein on SW1990 cell proliferation.
RESULTS: High TYROBP expression in PDAC tissues correlated with increased M2 macrophage infiltration, as indicated by elevated CD68 and CD206 levels. TYROBP overexpression promotes M2 macrophage polarization and glycolytic reprogramming via STAT3/PKM2, validated in vitro and in vivo. TYROBP overexpression also promoted the nuclear translocation of STAT3 and PKM2, enhancing glycolytic activity in SW1990 cells. STAT3 and PKM2 cooperated to regulate CXCL8 expression via direct binding to the CXCL8 promoter region. Molecular docking demonstrated baicalein's binding to STAT3, and in vivo studies showed that baicalein significantly inhibited SW1990 cell growth and modulated key signaling pathways.
CONCLUSIONS: Our study reveals that high TYROBP expression is associated with increased M2 macrophage infiltration in PDAC, promoting a pro-tumorigenic TME. TYROBP overexpression drives macrophage polarization towards the M2 phenotype, enhances glycolytic activity, and modulates key signaling pathways. Baicalein, targeting STAT3, shows potential as a therapeutic agent for PDAC by inhibiting cell proliferation and modulating the TME. These findings highlight TYROBP as a key regulator in PDAC progression and suggest potential therapeutic strategies targeting TYROBP and its associated pathways.

Keywords:  Baicalein; Glycolytic metabolism; Pancreatic ductal adenocarcinoma (PDAC); TYRO protein tyrosine kinase binding protein (TYROBP); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.cellsig.2025.111949