Cell Communication and Signaling最新文献

{"title":"Quantitative characterisation of extracellular vesicles designed to decoy or compete with SARS-CoV-2 reveals differential mode of action across variants of concern and highlights the diversity of Omicron.","authors":"Melanie Schürz, Isabel Pagani, Eva Klinglmayr, Heloisa Melo Benirschke, Martin Mayora Neto, Luis J V Galietta, Arianna Venturini, Nicoletta Pedemonte, Valeria Capurro, Sandra Laner-Plamberger, Christoph Grabmer, Essi Emminger, Martin Wolf, Marianne Steiner, Cyrus Kohlmetz, Niklas Mayr, Liliia Paniushkina, Katharina Schallmoser, Dirk Strunk, Hans Brandstetter, Martin Hintersteiner, Nigel Temperton, Elisa Vicenzi, Nicole Meisner-Kober","doi":"10.1186/s12964-025-02223-x","DOIUrl":"https://doi.org/10.1186/s12964-025-02223-x","url":null,"abstract":"<p><strong>Background: </strong>The converging biology between enveloped viruses and extracellular vesicles (EVs) has raised interest in the application of engineered EVs as antiviral therapeutics. Following the recent COVID-19 pandemic, EVs engineered with either the ACE2-receptor or Spike-protein have been proposed as strategy to either decoy SARS-CoV-2, or to compete with its cell entry. For generic use as a platform for future pandemic preparedness, a systematic and quantitative comparison of both strategies is required to assess their limitations and benefits across different variants of concern.</p><p><strong>Methods: </strong>Here we generated EVs decorated with either the ACE2-receptor or the Spike-protein of (Wuhan)-SARS-CoV-2 and used single vesicle imaging for in-depth quantitative characterisation. These vesicles were then systematically tested for anti-viral activity across SARS-CoV-2 variants of concern using both, pseudotype and live virus cellular infection models including primary human bronchial and nasal explants.</p><p><strong>Results: </strong>Spike-protein EVs or ACE2-EVs recovered from transiently transfected HEK293T cells comprised only a small fraction of the EV secretome (5% or 20%, respectively) and were primarily derived from the plasma membrane rather than multivesicular bodies. Redirecting intracellular trafficking of the Spike protein by mutating its transmembrane or subcellular localisation domains did not increase the yields of Spike-EVs. Both types of vesicles inhibited SARS-CoV-2 (D614G) in a dose dependent manner with kinetics and immunohistochemistry consistent with an inhibition at the initial cell entry stage. ACE2-EVs were more potent than Spike-EVs and at least 500-1000 times more potent than soluble antibodies in a pseudotype model. Surprisingly, ACE2-EVs switched from an inhibitory to an enhancer activity for the Omicron BA.1 variant whereas Spike-EVs retained their activity across all variants of concern.</p><p><strong>Conclusions: </strong>While our data show that both types of engineered EVs potently inhibit SARS-CoV, the decoy versus competition strategy may result in diverging outcomes when considering viral evolution into new variants of concern. While Spike-EVs retain their competition for receptor binding even against higher affinity viral Spike mutations, the formation of complexes between ACE2-EVs and the virus may not only result in inhibition by decoy. As EVs are actively internalised by cells themselves, they may shuttle the virus into cells, resulting in a productive alternative cell entry route for variants such as Omicron, that diverge from strict plasma membrane protease cleavage to the use of endosomal proteases for release of their genome.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"323"},"PeriodicalIF":8.2,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aurantio-obtusin modulates Wilms Tumour 1 within the breast tumour microenvironment reducing immunosuppression and tumour growth.","authors":"Rui Li, Dómhnall J O'Connor, Barry Digby, Pilib Ó Broin, Xiao Hu, Ning Ge, Paul G Loftus, Vatsal Kumar, Eoin McEvoy, Stephen J Elliman, Michael J Kerin, Laura R Barkley","doi":"10.1186/s12964-025-02292-y","DOIUrl":"10.1186/s12964-025-02292-y","url":null,"abstract":"<p><strong>Introduction: </strong>Cancer associated fibroblasts (CAFs) contribute to tumourigenesis and immune tolerance within the tumour microenvironment (TME). Therefore, inhibiting the pro-tumourigenic function of CAFs can be a viable therapeutic approach. However, targeting CAFs is challenging due to the lack of specific markers. The objective of this study is to identify CAF specific therapeutic targets that have the potential to enhance tumour immunity and reduce tumour growth.</p><p><strong>Methods: </strong>RNA sequencing was performed on CAFs and normal fibroblasts (NFs) from the same breast cancer patient. Wilms tumour-1 (WT1) was identified as a gene upregulated in CAFs. WT1 levels in CAFs were manipulated using plasmid overexpression of-or siRNA downregulation of WT1. Co-culture assays were performed to evaluate the role of CAF-derived WT1 in T cell proliferation and differentiation using flow cytometry. Western blot and ELISA were performed to interrogate the mechanism of action of WT1 within CAFs. Three-dimensional patient-derived organoids (PDOs) that encompassed the tumour immune-microenvironment were established to determine the therapeutic potential of targeting CAF-derived WT1.</p><p><strong>Results: </strong>WT1, a transcription factor, regulates signal transducer and activator of transcription (STAT) 1/3 levels, promotes programmed death ligand 1 (PD-L1) expression and indoleamine 2,3-dioxygenase (IDO) expression in CAFs. CAF-derived WT1 reduces the proliferation of CD4⁺ and CD8⁺ T cells and enhances the differentiation of naïve T cells into regulatory T cells (Tregs), thus producing an immunosuppressive TME. Reducing CAF WT1 levels results in less immunosuppressive CAFs, smaller PDOs and increased levels of cytotoxic granzyme B⁺ (GZMB⁺) T cells within the TME. Standard chemotherapeutic agents, paclitaxel (PTX) and doxorubicin (DOX), increase WT1 levels in CAFs enhancing their ability to suppress T cell proliferation. However, Aurantio-obtusin (AO, a DOX analogue) decreases WT1 expression in CAFs reducing their ability to suppress T cell proliferation. AO causes decreased PDO size which correlates with increased levels of T cells within the TME.</p><p><strong>Conclusions: </strong>Therapeutic targeting of the WT1/STAT1/3/PD-L1/IDO axis in CAFs with AO has the potential to enhance T cell activity and reduce Treg percentage within the TME, thereby enhancing tumour immunity and reducing tumourigenesis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"309"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A senior moment: What is the program of programmed cell death?","authors":"Richard A Lockshin","doi":"10.1186/s12964-025-02255-3","DOIUrl":"10.1186/s12964-025-02255-3","url":null,"abstract":"<p><p>A previously generated sequence of putative mRNA from intersegmental muscles of Manduca sexta moths just before the death of the muscles has been identified as the N-terminal sequence of a copper chaperone for superoxide dismutase. This observation suggests that prior blockage of a scavenger of free radicals may set the muscle up for free radical damage just before it begins very vigorous activity resulting in high oxygen demand.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"310"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphorylated IRF3 promotes GSDME-mediated pyroptosis through RIPK1/FADD/caspase-8 complex formation during mitotic arrest in ovarian cancer.","authors":"Wenjian Gong, Dongchen Zhou, Qiuyang Xu, Linghui Wang, Mengshi Luo, Yuewen Zhang, Zhiqi Liao, Fan Xiong, Guangnian Zhao, Bingbing Zhao, Qinglei Gao, Yong Fang","doi":"10.1186/s12964-025-02322-9","DOIUrl":"10.1186/s12964-025-02322-9","url":null,"abstract":"<p><p>Inducing mitotic arrest with anti-mitotic drugs is an effective strategy for cancer therapy. However, the ultimate fate of cells that undergo prolonged mitotic arrest remains largely uncertain. In this study, paclitaxel and nocodazole were used to induce prolonged mitotic arrest in ovarian cancer cells, triggering mitotic catastrophe, during which these cells exhibited hallmarks of pyroptosis. Subsequently, small interfering RNA (siRNA)-mediated downregulation of Gasdermin E (GSDME) inhibited pyroptosis, suggesting that GSDME plays an essential role in this process. The upstream signaling pathway was further investigated through caspase-3 inhibition and caspase-8 knockdown, which demonstrated that pyroptosis induced by paclitaxel and nocodazole was mediated by the caspase-8/caspase-3/GSDME pathway. Moreover, during mitotic arrest, phosphorylation of IRF3, mediated by cGAS/TBK1, led to the formation of the RIPK1/FADD/caspase-8 complex, which subsequently activated caspase-8 and initiated downstream GSDME-mediated pyroptosis. Knockdown of components of this complex or mutation of the IRF3 phosphorylation site inhibited pyroptosis. Furthermore, in vivo experiments also demonstrated that paclitaxel inhibited tumor growth by inducing GSDME-mediated pyroptosis and activating the anti-tumor immune infiltration. TCGA data further suggested that ovarian cancer cases treated with paclitaxel, showing high expression of GSDME and caspase-3, exhibited a more favorable tumor immune microenvironment. This study not only elucidated the specific mechanism of pyroptosis mediated by phosphorylated IRF3 during prolonged mitotic arrest but also revealed that mitotic arrest-induced pyroptosis could enhance immune infiltration in ovarian cancer, providing valuable insights for clinical treatment strategies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"306"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senescence-associated alterations in histone H3 modifications, HP1 alpha levels and distribution, and in the transcriptome of vascular smooth muscle cells in different types of senescence.","authors":"Agnieszka Gadecka, Marta Koblowska, Helena Kossowska, Roksana Iwanicka-Nowicka, Dorota Janiszewska, Grażyna Mosieniak, Krzysztof Bojakowski, Krzysztof Goryca, Anna Bielak-Zmijewska","doi":"10.1186/s12964-025-02315-8","DOIUrl":"10.1186/s12964-025-02315-8","url":null,"abstract":"<p><strong>Background: </strong>Cellular senescence is a fundamental process leading to organismal aging and age-related diseases. Alterations accompanying cellular senescence concern, among others, nucleus architecture, chromatin structure, DNA damage and gene expression. Some changes are universal for all types of senescence, but some characteristics are typical for a given senescence inductor or cell type. The aim of the study was to analyze senescence-associated alterations in chromatin modifications and look for differences depending on senescence type (replicative, RS and stress-induced premature senescence, SIPS) in vascular smooth muscle cells (VSMCs) in vitro. The alterations were compared with those observed in VSMCs derived from atherosclerotic plaques (ex vivo) and, to assess their universality, with those in senescent fibroblasts.</p><p><strong>Methods: </strong>We investigated the level and distribution of HP1α and H3 modifications that are markers of hetero- and euchromatin (H3K9me3, H3K27me3, H3K4me3, H3K9Ac - WB and IF), alterations in the transcriptomic profile (DNA microarray, qPCR), H3K4me3, H3K9me3 and HP1α protein distribution in the genome (ChIP-seq), and expression of enzymes involved in histone post-translational modifications (DNA microarray, qPCR, WB, IF).</p><p><strong>Results: </strong>Our results have shown that the decline in H3K4me3 and H3K9me3 modifications and in HP1α is a universal hallmark of senescence in all tested cell and senescence types, although the extent of the change depends on the senescence inductor. The distribution of H3K4me3 and H3K9me3 in the genome of VSMCs depends on the senescence type, and the transcriptomic analysis identified genes and processes specific to each type.</p><p><strong>Conclusions: </strong>We characterized senescence and cell type-dependent changes in chromatin-associated proteins and enzymes involved in histone H3 decoration which, in consequence, impact senescence-associated gene expression. We can conclude that certain similar alterations occur in senescent VSMCs ex vivo, although inter-individual differences usually obscure them. Our results clearly showed that differences existed not only between young and senescent cells but also between SIPS and RS ones. The subtle differences between various SIPS types suggest that various stressors activate the same cellular mechanisms. This study can serve as a starting point to search for factors that may be used to distinguish between SIPS and RS, which in turn could be helpful in defining conditions responsible for accelerated aging.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"321"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-23 promotes neuronal ferroptosis via IL-23R/STAT3 signaling after traumatic brain injury.","authors":"Bo Chen, Guihong Shi, Jianye Xu, Xu Zhang, Yanlin Zhu, Lei Li, Cong Wang, Dilmurat Gheyret, Jinchao Wang, Xilei Liu, Yiyao Cao, Rui Tan, Yuan Zhou, RongCai Jiang, Shenghui Li, Tuo Li, Xiao Liu, Xin Chen, Guili Yang, Jianning Zhang, Shu Zhang","doi":"10.1186/s12964-025-02319-4","DOIUrl":"10.1186/s12964-025-02319-4","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) causes significant neuronal death, but the underlying mechanisms remain poorly understood. The role of interleukin-23 (IL-23) signaling in post-traumatic neuronal injury requires investigation.</p><p><strong>Methods: </strong>We examined IL-23 levels in clinical samples from TBI patients and healthy controls. Using a mouse TBI model, we investigated the effects of IL-23 neutralization and explored the cellular mechanisms through analysis of IL-23 receptor expression, JAK2/STAT3 pathway activation, and macrophage infiltration.</p><p><strong>Results: </strong>We found elevated IL-23 levels in both serum and brain tissues of TBI patients. TBI induced neuronal IL-23 receptor expression and activated the JAK2/STAT3 pathway. Infiltrating macrophages were identified as the main IL-23 source, recruited by neuron-derived C-C motif chemokine ligand 2 (CCL2). IL-23 neutralization or CCL2 blockade reduced neuronal ferroptosis and improved neurological outcomes in the mouse model.</p><p><strong>Conclusions: </strong>Our findings reveal a novel CCL2-macrophage-IL-23 axis in TBI pathogenesis, where IL-23 promotes neuronal ferroptosis through direct receptor-mediated effects. Targeting this pathway represents a potential therapeutic strategy for TBI treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"317"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP3 promotes autophagy-mediated TNBC metastasis via m6A-dependent, cap-independent c-Met translation.","authors":"Zi-Wen Wang, Yi-Han Li, Meng-Yuan Cai, Xu Zhang, Ruo-Xi Xu, Hai-Yan Yang, Yu-Zhou Huang, Liang Shi, Ji-Fu Wei, Qiang Ding","doi":"10.1186/s12964-025-02316-7","DOIUrl":"10.1186/s12964-025-02316-7","url":null,"abstract":"<p><strong>Background: </strong>Metastatic tumors pose clinical treatment challenges due to their high adaptability to diverse environments. The cooperation of epigenetic modifications and metabolic adaptations enables tumor cells to dynamically adjust for survival in variable environments, which is crucial for tumor metastasis and worth exploring in depth.</p><p><strong>Methods: </strong>RNA immunoprecipitation sequencing, transmission electron microscopy photograph and GFP-mCherry-LC3 fluorescence imaging were employed to reveal the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in triple-negative breast cancer (TNBC) cells. Then, in the presence of rapamycin, further experiments showed that IGF2BP3's role in TNBC metastasis was autophagy-mediated. Methylated RNA immunoprecipitation sequencing, luciferase assays and co-immunoprecipitation mass spectrometry showed that IGF2BP3 promoted mRNA translation initiation in an N6-methyladenosine (m6A)-dependent manner.</p><p><strong>Results: </strong>We found that IGF2BP3 could link epigenetic modification and metabolic adaptation to promote autophagy-mediated TNBC metastasis. As an m6A binding protein that is specifically highly expressed in TNBC, IGF2BP3 could bind to the m6A motif of c-Met mRNA, regulating autophagy-mediated epithelial-to-mesenchymal transition via the c-Met/PI3K/AKT/mTOR pathway. Moreover, IGF2BP3 recruited eIF4G2 as a collaborator, promoting c-Met protein expression by facilitating m6A-dependent and cap-independent mRNA translation initiation, rather than affecting mRNA stability.</p><p><strong>Conclusions: </strong>Our study expands the understanding of IGF2BP3's role in TNBC metastasis by establishing its function in regulating autophagy. Notably, IGF2BP3 could bind to the m6A motif on the 5' and 3' untranslated regions (UTRs) of c-Met mRNA to facilitate its translation in a cap-independent manner.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"303"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.","authors":"Mincong Shu, Yuhan Liu, Jianbin Wang","doi":"10.1186/s12964-025-02327-4","DOIUrl":"10.1186/s12964-025-02327-4","url":null,"abstract":"<p><p>Serine is a non-essential amino acid, serving as a precursor for other amino acids, lipids, and nucleotide synthesis. Its supply is ensured by two main mechanisms: exogenous uptake and endogenous synthesis. The serine synthesis pathway (SSP) connects glycolysis with the one-carbon cycle and plays an important role in cellular homeostasis by regulating substance synthesis, redox homeostasis, and gene expression. The de novo SSP involves three successive enzymatic reactions catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). Post-translational modifications (PTMs), as essential regulatory mechanisms of proteins, play pivotal roles in physiological and pathological processes. This review focuses on the regulatory mode of PTMs on PHGDH, PSAT1, and PSPH, including phosphorylation, ubiquitination, acetylation, methylation, S-palmitoylation, S-nitrosylation, deamidation, SUMOylation, and lactylation. We summarize how these PTMs participate in the metabolic reprogramming of SSP. It helps us better understand the molecular mechanisms and physiological significance of the PTM network in serine synthetic metabolism, providing guidance for subsequent research and development in the future.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"311"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.","authors":"Yiyi Shou, Ruiqi Liu, Hao Xiong, Keke Xu, Xiaoyan Chen, Luanluan Huang, Yitian Zhang, Hailong Sheng, Haibo Zhang, Yanwei Lu","doi":"10.1186/s12964-025-02328-3","DOIUrl":"10.1186/s12964-025-02328-3","url":null,"abstract":"<p><p>Cancer cells experience metabolic reprogramming to enhance the synthesis of nitrogen and carbon, facilitating the production of macromolecules essential for tumor proliferation and growth. A central strategy in this process involves reducing catabolic activities and managing nitrogen, thereby improving the efficiency of nitrogen utilization. The urea cycle (UC), conventionally recognized for its role in detoxifying excess nitrogen in the liver, is pivotal in this metabolic transition. Beyond the hepatic environment, the differential expression of UC enzymes facilitates the utilization of nitrogen for the synthesis of metabolic intermediates, thereby addressing the cellular metabolic requirements, especially under conditions of nutrient scarcity. In oncogenic contexts, the expression and regulation of UC enzymes undergo substantial modification, promoting metabolic reprogramming to optimize nitrogen assimilation into cellular biomass. This reconfigured UC not only enhances tumor cell survival but also plays a pivotal role in the reorganization of the tumor microenvironment (TME), thereby aiding in immune evasion. This review examines the mechanistic underpinnings of urea cycle dysregulation (UCD) in cancer, highlighting its dynamic roles across various tumor types and stages, as well as the therapeutic implications of these alterations. Understanding how UC relaxation promotes metabolic flexibility and immune evasion may help develop novel therapeutic strategies that target tumor metabolism and enhance anti-cancer immunity.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"307"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of electroacupuncture-induced neuroprotection in acute stroke rats: the role of astrocyte-mediated mitochondrial transfer.","authors":"Yang Guo, Tiancong Fu, Yupei Cheng, Yuxuan Li, Runchen Zhang, Qingtao Ma, Guanran Wang, Wenhua Ning, Wen Fan, Juntao Yang, Mengxiong Zhao, Bohan Liu, Can Wang, Liang Gao, Zhifang Xu, Yi Guo, Xiaoyu Dai, Jiangwei Shi","doi":"10.1186/s12964-025-02287-9","DOIUrl":"10.1186/s12964-025-02287-9","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke significantly threatens human health, and current treatments remain limited, necessitating novel strategies. Mitochondrial transfer between neurons represents a crucial endogenous neuroprotective mechanism.</p><p><strong>Objective: </strong>This study investigated whether electroacupuncture enhances mitochondrial transfer from astrocytes to damaged neurons during acute cerebral ischemia, promoting neuroprotection.</p><p><strong>Methods: </strong>A middle cerebral artery occlusion (MCAO) model in Sprague-Dawley (SD) rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro were employed. Neurobehavioral assessments, electron microscopy, multiplex immunofluorescence, tissue quantification, western blotting, qRT-PCR, transcriptomics, and proteomics were conducted to evaluate mitochondrial distribution, function, and intercellular transfer under electroacupuncture preconditioning and intervention.</p><p><strong>Results: </strong>Electroacupuncture significantly improved neurological outcomes and reduced brain tissue damage in MCAO rats. It facilitated mitochondrial transfer from astrocytes to neurons, increased functional mitochondria within neurons, and reduced neuronal apoptosis. These effects may involve regulation of the CD38-cADPR-Ca2 + signaling pathway and proteins associated with tunneling nanotubes (TNTs), such as F-actin, Miro1, TRAK1, and KIF5b.</p><p><strong>Conclusion: </strong>Electroacupuncture enhances mitochondrial transfer and function, exerting neuroprotective effects during acute ischemic stroke. This study highlights the potential of electroacupuncture as a therapeutic approach and identifies novel targets for brain protection strategies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"316"},"PeriodicalIF":8.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}