Cell Communication and Signaling最新文献

{"title":"Differential regulation of mTORC2 signalling by type I and type II calreticulin (CALR) driver mutations of myeloproliferative neoplasm.","authors":"Saadia Naseer, Aditi Singh, Saurabh Shrivastva, Rishi Kant Singh, Shayeri Chowdhury, Chinmoy Sankar Dey, Anita Roy","doi":"10.1186/s12964-025-02212-0","DOIUrl":"10.1186/s12964-025-02212-0","url":null,"abstract":"<p><p>Calreticulin (CALR) is an endoplasmic reticulum chaperone. Frameshift mutations in CALR were discovered in patients with myeloproliferative neoplasm showing increased platelet counts. The frameshift was observed in the last exon of CALR, leading to a novel C-terminal tail. Calreticulin mutations were categorised into Type I and Type II depending upon the extent of retention of CALR WT sequences. Clinically, Type I mutations induced myelofibrosis, while Type II mutations were associated with early onset of the disease. Both mutations induced ligand-independent activation of the thrombopoietin receptor (TpoR) and consequently enhanced platelet production. However, no specific difference in signalling mechanism could be demonstrated between them. Using over-expression of CALR WT, CALR ∆52 (Type I) and CALR ins5 (Type II) in HEK cells, we showed that Type I CALR mutations downregulated the basal mTORC2 signalling without affecting mTORC1. The decrease in basal mTORC2 signalling was attributed to CALR ∆52-induced increased expression of c-JUN through occupation of the enhancer sequences of jun. Furthermore, increased c-JUN expression decreased the expression of RICTOR, a component of mTORC2. Strikingly, overexpression of RICTOR or knockdown of c-JUN reversed the inhibitory effect of CALR ∆52 on mTORC2 activity. Finally, we demonstrated that CALR ∆52 decreased the glucose uptake and cellular ATP levels in a c-JUN-mTORC2-dependent manner. These findings not only contribute to our understanding of the molecular mechanisms underlying mutant CALR driven myeloproliferative neoplasm but also provide potential therapeutic targets against the disease.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"221"},"PeriodicalIF":8.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013619","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":"Dual inhibition of GTP-bound KRAS and mTOR in lung adenocarcinoma and squamous cell carcinoma harboring KRAS G12C.","authors":"Masaoki Ito, Yoshihiro Miyata, Shoko Hirano, Nagisa Morihara, Misako Takemoto, Fumiko Irisuna, Kei Kushitani, Kenichi Suda, Junichi Soh, Yukio Takeshima, Yasuhiro Tsutani, Morihito Okada","doi":"10.1186/s12964-025-02187-y","DOIUrl":"https://doi.org/10.1186/s12964-025-02187-y","url":null,"abstract":"<p><strong>Background: </strong>Kirsten rat sarcoma (KRAS) mutations are somatic variants in lung adenocarcinoma. One of the most prevalent mutations, G12C, has led to the clinical approval of targeted inhibitors for advanced stages in lung cancer. Research has increasingly focused on the efficacy of combination therapies that target multiple tumorigenic pathways. Cases harboring KRAS G12C mutation are heterogenous. We explored alternative changes in genetic pathways and evaluated the effectiveness of combination therapy using several types of cell lines and KRAS inhibitors.</p><p><strong>Methods: </strong>We comprehensively investigated genetic changes induced by KRAS G12C inhibition using RNA sequences and the candidate to inhibit in combination therapy was explored. Three lung cancer cell lines (two adenocarcinoma and one squamous cell carcinoma) and three KRAS G12C inhibitors (AMG 510, MRTX849, and ARS-1620) were used. KRAS G12C and candidate gene were simultaneously inhibited in cell lines and the efficiency of combination therapy was evaluated using clonogenic assays and MTS assay. Pathway activation was assessed via western blotting. A combination index (CI) < 0.8 was considered statistically synergistic.</p><p><strong>Results: </strong>RNA sequences revealed treatment with two of the three KRAS G12C inhibitors led to a significant increase in mTOR expression across all three cell lines. mTOR was targeted in combination therapy; each KRAS G12C inhibitor and mTOR inhibitor (RAD001) combination exhibited synergism (CI < 0.8) in MTS and clonogenic assays. Single inhibition of mTOR induced activation of guanosine triphosphate (GTP)-RAS, thereby activating the RAS-MEK-ERK and PI3K-AKT-mTOR pathways in WB, suggesting mTOR activation is crucial for KRAS-driving lung cancer. A combination strategy targeting KRAS G12C and mTOR abrogated GTP-RAS, pmTOR (Ser2448), and pERK (Thr202/Tyr204) more efficiently.</p><p><strong>Conclusions: </strong>KRAS G12C inhibitor plus RAD001 consistently revealed synergism. Targeting KRAS G12C and mTOR abrogates the RAS-MEK-ERK and PI3K-AKT-mTOR pathways. Our data suggests that a combined strategy targeting GTP-bound KRAS G12C and mTOR shows promise for primary lung cancers with KRAS G12C mutations. This approach may also be effective even for lung cancers harboring KRAS G12C mutation but having different profiles.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"220"},"PeriodicalIF":8.2,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042911","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":"HIF-1α regulated GLUT1-mediated glycolysis enhances Treponema pallidum-induced cytokine responses.","authors":"Shun Xiong, Zhaoping Liu, Jiangchen Yao, Shaobin Huang, Xuan Ding, Han Yu, Ting Lin, Xiaohong Zhang, Feijun Zhao","doi":"10.1186/s12964-025-02211-1","DOIUrl":"https://doi.org/10.1186/s12964-025-02211-1","url":null,"abstract":"<p><p>Syphilis, caused by Treponema pallidum (Tp), represents a significant public health challenge. The clinical manifestations of syphilis are attributed to local inflammatory responses induced by Tp, notably monocyte infiltration into local lesions and the secretion of inflammatory cytokines. However, the mechanisms driving cytokine production in response to Tp infection remain largely unknown. Given that increased glycolysis is associated with inflammatory responses, we aimed to investigate the role of glycolysis in Tp-induced secretion of inflammatory cytokines. In this study, we found that Tp promotes the secretion of inflammatory cytokines IL-6, IL-8, and CCL2 from monocytes while enhancing glycolysis through increased GLUT1 plasma membrane expression and glucose uptake. Importantly, inhibiting glycolysis and GLUT1 reduced the Tp-induced secretion of monocyte inflammatory cytokines. Additionally, Tp significantly increased HIF-1α expression and induced its nuclear translocation, thereby promoting glycolysis by upregulating the expression of GLUT1 and LDHA glycolytic enzymes. Knockdown of HIF-1α inhibits Tp-induced monocyte cytokine secretion, highlighting the crucial role of HIF-1α-mediated glycolysis in the cytokine response to Tp. Also, expression of HIF-1α and an increase in glycolysis were confirmed in patients with syphilis. In conclusion, we demonstrated that HIF-1α-regulated GLUT1-mediated glycolysis enhances inflammatory cytokine secretion following Tp infection. Our findings not only elucidate the mechanism of glycolysis in Tp-induced inflammatory responses in monocytes but also contribute to the development of a potential biomarker in syphilis diagnosis and treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"219"},"PeriodicalIF":8.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993001","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":"Accumulation of long-chain unsaturated fatty acids in the airway inflammatory microenvironment drives eosinophil etosis and corticosteroid resistance.","authors":"Yurong Bai, Pengda Fang, Shasha Li, Zhenhao Xiao, Wenyi Chen, Wenlong Li, Xinyue Wang, Jingyuan Chen, Yue Li, Junhai Chen, Weiqiang Huang, Xin Luo, Shigeharu Ueki, Deyu Fang, Qintai Yang, Yana Zhang","doi":"10.1186/s12964-025-02217-9","DOIUrl":"https://doi.org/10.1186/s12964-025-02217-9","url":null,"abstract":"<p><strong>Background: </strong>Eosinophilic inflammation is a feature of chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with eosinophilic CRSwNP (ENP) tend to be refractory and prone to recurrence. Although there is increasing evidence linking lipid metabolic irregularities to eosinophilia, the particular lipid responsible for promoting eosinophilic inflammation and the precise molecular mechanisms involved remain unclear.</p><p><strong>Methods: </strong>Lipidomic atlas and metabolic pathway enrichment were identified by liquid chromatography-tandem mass spectrometry and RNA sequencing, respectively. Eosinophil extracellular trap cell death (EETosis) was detected by immunofluorescence microscopy and transmission electron microscopy. Functional analyses were performed on purified eosinophils.</p><p><strong>Results: </strong>The unbiased lipidomic atlas identified a specific accumulation in long-chain fatty acids (LCFAs) in ENP. Consistently, RNA-seq analysis confirmed the enrichment in long-chain unsaturated fatty acid metabolism pathway in ENP. In this lipid-rich airway inflammatory environment, EETosis including ETotic eosinophils, EETs release and Charcot-Leyden crystals (CLCs) generation was enhanced in ENP, and associated with disease severity. Further, we found that both saturated and unsaturated LCFAs, such as arachidonic acid, are critical fuel sources to trigger eosinophil activation and filamentous DNA release, whereas only arachidonic acid could induce crystalline Galectin10 (CLCs). Mechanistically, arachidonic acid induces EETosis through a mechanism independent of reactive oxygen species but the IRE1α/XBP1s/PAD4 pathway. Both the long-acting dexamethasone and short-acting hydrocortisone, while facilitate eosinophil apoptosis, are ineffective to block arachidonic acid-induced EETosis.</p><p><strong>Conclusions: </strong>Our findings demonstrate a previously unknown role of the LCFA arachidonic acid in mediating EETosis and glucocorticoid insensitivity to drive ENP progression, which may lead to novel insights regarding the treatment of patients with refractory eosinophilic inflammation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"217"},"PeriodicalIF":8.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022958","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":"IKZF1 as a potential therapeutic target for dendritic cell-mediated immunotherapy in IgA nephropathy.","authors":"Fei Peng, Chunjia Sheng, Jiayi He, Yena Zhou, Yilun Qu, Shuwei Duan, Yinghua Zhao, Jikai Xia, Jie Wu, Guangyan Cai, Lingling Wu, Chuyue Zhang, Xiangmei Chen","doi":"10.1186/s12964-025-02196-x","DOIUrl":"https://doi.org/10.1186/s12964-025-02196-x","url":null,"abstract":"<p><strong>Background: </strong>Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis globally and a major cause of renal failure. Immune dysregulation drives its pathogenesis. This study identifies novel genes as potential diagnostic and therapeutic targets, elucidating immune mechanisms in IgAN.</p><p><strong>Methods: </strong>Immune cell infiltration analysis was conducted to explore the abnormal regulation of immune cells in IgAN. Weighted gene co-expression network analysis (WGCNA) was integrated with protein-protein interaction (PPI) analysis to identify hub genes associated with dendritic cells (DCs) in IgAN. Receiver operating characteristic (ROC) curve analysis and machine learning algorithms were employed to screen for DC-related diagnostic biomarkers from the dataset. Multiple bioinformatics methods were utilized to reveal shared molecular pathways. The findings were further validated through in vivo and vitro intervention experiments.</p><p><strong>Results: </strong>WGCNA, Cytoscape, and three machine learning models collectively identified hub genes (IKZF1, MPEG1, CCR2, CCR5, and CCR7) that are significantly associated with DC immunity. Among these, IKZF1 was pinpointed as a key hub gene and a potential diagnostic biomarker for DC-related immune responses. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA) further revealed substantial differences in the biological processes, signaling pathways, and immune characteristics of DCs. RT-qPCR and immunofluorescence analyses confirmed enhanced infiltration of IKZF1⁺ DCs in the tissues of both IgAN mice and anti-Thy1 nephritis rats. Mechanistically, IKZF1 promotes inflammation by mediating the production of pro-inflammatory factors and enhancing antigen presentation in DCs; this effect can be mitigated by siIKZF1 or lenalidomide treatment under LPS-induced inflammatory conditions in vitro. Consistently, treatment with lenalidomide, a molecular degrader of IKZF1, in anti-Thy1 nephritis models effectively alleviated renal damage and reduced inflammatory cell infiltration.</p><p><strong>Conclusions: </strong>This study delineated key patterns of immune cell infiltration in IgAN and identified diagnostic biomarkers associated with DCs, offering valuable insights into the potential therapeutic targeting of IKZF1⁺ DCs.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"216"},"PeriodicalIF":8.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998120","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":"Strong protection by bazedoxifene against chemically-induced ferroptotic neuronal death in vitro and in vivo.","authors":"Xiangyu Hao, Yifan Wang, Ming-Jie Hou, Yong Xiao Yang, Lixi Liao, Tongxiang Chen, Pan Wang, Xiaojun Chen, Bao Ting Zhu","doi":"10.1186/s12964-025-02209-9","DOIUrl":"https://doi.org/10.1186/s12964-025-02209-9","url":null,"abstract":"<p><p>Ferroptosis, a form of regulated cell death associated with glutathione depletion and excess lipid peroxidation, can be induced in cultured cells by chemicals (e.g., erastin and RSL3). It has been shown that protein disulfide isomerase (PDI) is a mediator of chemically-induced ferroptosis and also a crucial target for ferroptosis protection. The present study reports that bazedoxifene (BAZ), a selective estrogen receptor modulator, is an inhibitor of PDI and can strongly rescue neuronal cells from chemically-induced oxidative ferroptosis. We find that BAZ can directly bind to PDI and inhibit its catalytic activity. Computational modeling analysis reveals that BAZ forms a hydrogen bond with PDI's His256 residue. Inhibition of PDI by BAZ markedly reduces iNOS and nNOS dimerization (i.e., catalytic activation) and NO accumulation, and these effects of BAZ are associated with reductions in cellular ROS and lipid-ROS and protection against chemically-induced ferroptosis. In addition, the direct antioxidant activity of BAZ may also partially contribute to its protection against chemically-induced ferroptosis. In vivo animal experiments show that mice treated with BAZ are strongly protected against kainic acid-induced oxidative hippocampal neuronal injury and memory deficits. Together, these results reveal that BAZ is a potent inhibitor of PDI and can strongly protect against chemically-induced ferroptosis in hippocampal neurons both in vitro and in vivo. This work provides evidence for an estrogen receptor-independent, PDI-mediated novel mechanism of neuroprotection by BAZ.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"218"},"PeriodicalIF":8.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023124","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":"Recurrence of acute allergic asthma depends on the role of ILC2 driven by Il1rl1 signaling.","authors":"Hui Gan, Zhifeng Huang, Qingjun Pan, Fei Ye, Zheng Zhu, Baoqing Sun","doi":"10.1186/s12964-025-02220-0","DOIUrl":"https://doi.org/10.1186/s12964-025-02220-0","url":null,"abstract":"<p><strong>Background: </strong>Asthma is a chronic inflammatory airway disease characterized by recurrent episodes that significantly impair disease control and reduce patients' quality of life. Despite its clinical importance, the mechanisms underlying asthma relapse remain poorly understood, and effective strategies to prevent exacerbations are still lacking.</p><p><strong>Methods: </strong>An acute allergic asthma relapse mouse model was established using ovalbumin sensitization and challenge. Single-cell transcriptomics was employed to investigate the cellular and molecular mechanisms driving asthma relapse. Flow cytometry and gene knockout experiments were conducted to validate the findings.</p><p><strong>Results: </strong>We successfully established an acute allergic asthma relapse mouse model. Single-cell transcriptomic analysis revealed that T cells and type 2 innate lymphoid cells (ILC2s) are pivotal during asthma relapse, serving as the primary cellular sources of type 2 inflammatory cytokines. Further subcluster analysis identified T-cell subcluster 4 and ILC2 subcluster 0 as the predominant contributors to type 2 cytokine production. Complex intercellular communication networks were observed, with macrophages, natural killer (NK) cells, and dendritic cells functioning as central signaling hubs. Pseudo-time trajectory analysis highlighted the critical role of ILC2s and the Il1rl1 signaling pathway in asthma relapse. These findings were corroborated by flow cytometry. Il1rl1-deficient mice displayed similar pulmonary inflammation to wild-type mice during the initial asthma episode; however, asthma relapse was significantly attenuated. Mechanistically, Il1rl1 deficiency resulted in a substantial reduction in both the number and functional capacity of ILC2s.</p><p><strong>Conclusion: </strong>The recurrence of acute allergic asthma is driven, at least in part, by ILC2s through Il1rl1 signaling. Genetic ablation of Il1rl1 significantly suppresses asthma relapse, suggesting that targeting Il1rl1 may represent a novel therapeutic strategy for preventing asthma exacerbations.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"215"},"PeriodicalIF":8.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059128","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":"Glycosylation as an intricate post-translational modification process takes part in glycoproteins related immunity.","authors":"Meng Tian, Xiaoyu Li, Liuchunyang Yu, JinXiu Qian, XiuYun Bai, Jue Yang, RongJun Deng, Cheng Lu, Hongyan Zhao, Yuanyan Liu","doi":"10.1186/s12964-025-02216-w","DOIUrl":"https://doi.org/10.1186/s12964-025-02216-w","url":null,"abstract":"<p><p>Protein glycosylation, the most ubiquitous and diverse type of post-translational modification in eukaryotic cells, proteins are input into endoplasmic reticulum and Golgi apparatus for sorting and modification with intricate quality control, are then output for diverse functional glycoproteins that are utilized by cells to precisely regulate various biological processes. In order to maintain the precise spatial structure of glycoprotein, misfolded and unfolded glycoproteins are recognized, segregated and degraded to ensure the fidelity of protein folding and maturation. This review enumerates the role of five immune-related glycoproteins and reveals the relevance of glycosylation to their antigen presentation, immune effector function, immune recognition, receptor binding and activation, and cell adhesion and migration. With the knowledgement of glycoproteins in immune responses and etiologies, we propose several relevant therapeutic strategies on targeting glycosylation process for immunotherapy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"214"},"PeriodicalIF":8.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022910","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":"The ester derivative Palmitoylcarnitine abrogates cervical cancer cell survival by enhancing lipotoxicity and mitochondrial dysfunction.","authors":"Sangavi Eswaran, Roshan Mascarenhas, Shama Prasada Kabekkodu","doi":"10.1186/s12964-025-02218-8","DOIUrl":"https://doi.org/10.1186/s12964-025-02218-8","url":null,"abstract":"<p><strong>Background: </strong>In cervical cancer (CC), Double C2 Like Domain Beta (DOC2B) functions as a metastatic suppressor. The present study aims to determine whether ectopic expression of DOC2B causes global metabolomic changes in extracellular vesicles (EVs) and corresponds with its tumor suppressive properties.</p><p><strong>Methods: </strong>Using a retroviral method, we first ectopically expressed DOC2B in SiHa cells, which do not normally express DOC2B.</p><p><strong>Results: </strong>We observed that ectopically expressed DOC2B significantly altered the global metabolite profile of EVs. Metabolomics identified significant enrichment of palmitoylcarnitine (PC) in EVs upon ectopic expression of DOC2B. We identified that SiHa and HeLa cells exhibited greater cytotoxicity to PC than gingival fibroblast, HaCaT, Cal27, and MCF7. PC treatment reduced the growth, proliferation, and migration of SiHa and HeLa cells, via increasing apoptosis and decreasing S-Phase cells. PC treatment resulted in morphological alterations, decreased length and number of filopodia, and expression of proteins related to cell cycle progression, proliferation, and the epithelial-to-mesenchymal transition. Further, PC treatment caused mitochondrial morphological changes, increased mitochondrial membrane potential, and decreased mtDNA content. The decreased GSH activity, glucose consumption rate, and lactate production upon PC treatment suggest that PC can induce metabolic reprogramming in CC cells. Increased oxidative stress, calcium overload, lipid droplet accumulation, mitochondrial lipotoxicity, and mitophagy suggest that PC can cause mitochondrial dysfunction. N-acetyl cysteine (NAC) treatment reversed the cytotoxic effect of PC, via decreasing lipid peroxidation rate and increasing GSH activity. PC treatment enhanced the cytotoxic effect of cisplatin in CC.</p><p><strong>Conclusion: </strong>DOC2B restoration or the use of PC may be employed as a novel therapeutic approach for CC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"213"},"PeriodicalIF":8.2,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041227","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":"Transmembrane thiol isomerase TMX1 inhibits fibrin formation by down-regulation of platelet phosphatidylserine exposure.","authors":"Zhenzhen Zhao, Yaqiong Zhang, Yixin Cheng, Xuyang Chen, Yi Lu, Yue Han, Yi Wu, Aizhen Yang","doi":"10.1186/s12964-025-02188-x","DOIUrl":"https://doi.org/10.1186/s12964-025-02188-x","url":null,"abstract":"<p><strong>Objective: </strong>Membrane exposure of phosphatidylserine (PS) on platelets is critical for the binding of coagulation factors leading to coagulation activation, however, the mechanism controlling PS exposure remains largely unknown. Using genetically modified mouse models, we previously reported that a transmembrane disulfide isomerase TMX1 inhibited integrin αIIbβ3 outside-in signaling which is important for PS exposure on platelets. In this study, we investigated the role of TMX1 in PS exposure and coagulation.</p><p><strong>Approach and results: </strong>We found that the deficiency of TMX1 in platelets enhanced fibrin formation and PS exposure at the site of injury. In vitro, TMX1 inhibited thrombin generation mediated by activated platelets, and attenuated PS exposure on platelets, the effect of which was prevented when integrin αIIbβ3 outside-in signaling was blocked, suggesting that TMX1 inhibition of integrin αIIbβ3 outside-in signaling suppresses PS exposure. Moreover, TMX1 deficiency increased the free thiols of TMEM16 F in platelets including Cys338, Cys349 and Cys352. In HEK293 T cells overexpressing C338S-, C349S-mutated TMEM16 F, the PS exposure was increased, suggesting that TMX1 oxidizes these disulfide bonds of TMEM16 F, decreasing its activity to externalize PS on the membrane.</p><p><strong>Conclusion: </strong>Together, our observations for the first time demonstrate that TMX1 inhibits PS exposure in platelets downregulating the procoagulant activity, by which TMX1 plays a critical role in maintaining vascular quiescence.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"212"},"PeriodicalIF":8.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045201","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}