Cell Communication and Signaling最新文献

{"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}

{"title":"Targeting microglial NAAA-regulated PEA signaling counters inflammatory damage and symptom progression of post-stroke anxiety.","authors":"Tianyue Yin, Shuaijie Sun, Li Peng, Mengmeng Yang, Mengyu Li, Xinlu Yang, Fengyun Yuan, Hongrui Zhu, Sheng Wang","doi":"10.1186/s12964-025-02202-2","DOIUrl":"https://doi.org/10.1186/s12964-025-02202-2","url":null,"abstract":"<p><p>Post-stroke anxiety (PSA) manifests as anxiety symptoms after stroke, with unclear mechanisms and limited treatment strategies. Endocannabinoids, reported to mitigate fear, anxiety, and stress, undergo dynamic alterations after stroke linked to prognosis intricately. However, endocannabinoid metabolism in ischemic microenvironment and their associations with post-stroke anxiety-like behavior remain largely uncovered. Our findings indicated that endocannabinoid metabolism was dysregulated after stroke, characterized by elevated N-palmitoylethanolamide (PEA) hydrolase N-acylethanolamine-acid amidase (NAAA) in activated microglia from ischemic area, accompanied by rapid PEA exhaustion. Microglial PEA metabolite exhaustion is directly associated with more severe pathological damage, anxiety symptoms and pain sensitivity. Naaa knockout or pharmacological supplementation to boost PEA pool content can effectively promote stroke recovery and alleviate anxiety-like behaviors. In addition, maintaining PEA pool content in ischemic area reduces overactivated microglia by confronting against mitochondria dysfunction and inflammasome cascade triggered IL-18 release and diffusion to contralateral hemisphere. Meanwhile, maintenance of microglial PEA pool content in ischemic-damaged lesion can preserve contralateral vCA1 synaptic integrity, enhancing anxiolytic pBLA-vCA1^Calb1+ circuit activity by alleviating microglial phagocytosis-mediated synaptic loss. Thus, we conclude that microglial NAAA-regulated lipid signaling in the ischemic focus remodels contralateral anxiolytic circuit to participate in post-stroke anxiety progression. Blocking PEA signaling breakdown promotes stroke recovery and mitigates anxiety-like symptoms.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"211"},"PeriodicalIF":8.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041297","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":"Head and neck squamous cell carcinoma-derived extracellular vesicles mediate Ca²⁺-dependent platelet activation and aggregation through tissue factor.","authors":"Tobias Weiser, Cosima C Hoch, Julie Petry, Maria Shoykhet, Benedikt Schmidl, Mina Yazdi, Khouloud Hachani, Julia Mergner, Marie-Nicole Theodoraki, Omid Azimzadeh, Gabriele Multhoff, Ali Bashiri Dezfouli, Barbara Wollenberg","doi":"10.1186/s12964-025-02215-x","DOIUrl":"https://doi.org/10.1186/s12964-025-02215-x","url":null,"abstract":"<p><strong>Background: </strong>Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, characterized by poor clinical outcomes, primarily driven by high rate of locoregional recurrence and metastasis. Extensive heterogeneity among the tumor cells as well as modulation of a highly immunosuppressive tumor microenvironment shape cancer progression. Shedding of extracellular vesicles (EVs) derived from tumor cells is a critical mediator of the disease initiating horizontal transfer of tumor components into platelets. This triggers platelet activation and thromboinflammation fueling tumor progression through multiple mechanisms.</p><p><strong>Methods: </strong>HNSCC-derived EVs isolated from HNSCC cell lines (SAS, UD-SCC 5) using size exclusion chromatography and characterized via flow cytometry, electron microscopy, nanoparticle tracking analysis and Western blotting, were used to induce platelet activation and aggregation, measured by aggregometry, flow cytometry, as well as the release of chemokines and Adenosine triphosphate, which were quantified using enzyme-linked immunosorbent assays (ELISA). Mechanistic investigations included inhibitor assays, thrombin activity measurements, and proteomic analyses.</p><p><strong>Results: </strong>We could show that EVs do not activate platelets through the FcγRIIa-IgG axis but platelet activation and aggregation is induced in a calcium-dependent manner, primarily mediated by EV-associated tissue factor. Proteomic analysis confirmed the presence of tissue factor in these vesicles, implicating its involvement in initiating the coagulation cascade, that leads to platelet activation and aggregation. This process was characterized by delayed aggregation kinetics and relied on thrombin activation, as the inhibition of thrombin and its receptors reduced platelet aggregation. HNSCC-derived EVs are pivotal in establishing a prothrombotic environment by promoting platelet activation and aggregation through tissue factor-dependent thrombin generation.</p><p><strong>Conclusion: </strong>These findings indicate a therapeutic potential of targeting EV-mediated pathways as a therapeutic approach to alleviate thrombotic complications in HNSCC patients. Subsequent animal studies will be crucial to validate and extend these observations, providing deeper insight into their clinical implications.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"210"},"PeriodicalIF":8.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060899","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":"Cytochrome P450 2E1 aggravates DXR-induced myocardial injury through imbalanced mitochondrial OPA1.","authors":"Jiaxin Ma, Yaheng Wang, Huijiao Lv, Yu Lei, Feifei Guan, Wei Dong, He Wang, Lianfeng Zhang, Dan Lu","doi":"10.1186/s12964-025-02197-w","DOIUrl":"https://doi.org/10.1186/s12964-025-02197-w","url":null,"abstract":"<p><strong>Background: </strong>Cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme, is linked to multiple pathophysiological states in the myocardium and may act as a sensor of heart diseases. However, the exact mechanisms of CYP2E1 in myocardial injury, particularly in chemotherapeutic agent-induced myocardial damage such as doxorubicin-induced cardiotoxicity, remain unclear.</p><p><strong>Methods: </strong>Using multiple animal models of cardiomyopathy and heart failure, we observed CYP2E1 expression in myocardial mitochondria. Myocardium-specific CYP2E1 overexpression and knockout rat models were employed to study its effects on myocardial injury, assessed via echocardiography and histopathology. Mechanistic insights were derived from transcriptome analysis, mass spectrometry, co-immunoprecipitation, signal transduction analysis, and molecular biology techniques.</p><p><strong>Results: </strong>CYP2E1 overexpression accelerated, while CYP2E1 knockout inhibited, myocardial injury in DXR-induced cardiomyopathy and isoprenaline-induced hypertrophic cardiomyopathy. Mechanistically, CYP2E1 was upregulated specifically in myocardial mitochondria during heart disease. This upregulation resulted in mitochondrial fragmentation and dysfunction under DXR-induced stress. CYP2E1 interacted with optic atrophy 1 (OPA1) in the inner mitochondrial membrane, leading to an imbalance between long and short OPA1 isoforms.</p><p><strong>Conclusions: </strong>CYP2E1 disrupts OPA1-mediated mitochondrial dynamics, causing mitochondrial fragmentation and apoptosis, which aggravate myocardial injury. Targeting CYP2E1 may offer a therapeutic strategy to mitigate myocardial damage, particularly in chemotherapeutic drug-induced cardiotoxicity.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"208"},"PeriodicalIF":8.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063275","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":"Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors.","authors":"Michaela Bosakova, Sara P Abraham, Davis Wachtell, Jennifer T Zieba, Alexander Kot, Alexandru Nita, Aleksandra Anna Czyrek, Adolf Koudelka, Vlad-Constantin Ursachi, Zuzana Feketova, Gustavo Rico-Llanos, Katerina Svozilova, Petra Kocerova, Bohumil Fafilek, Tomas Gregor, Jana Kotaskova, Ivan Duran, Petr Vanhara, Michael Doubek, Jiri Mayer, Karel Soucek, Deborah Krakow, Pavel Krejci","doi":"10.1186/s12964-025-02208-w","DOIUrl":"https://doi.org/10.1186/s12964-025-02208-w","url":null,"abstract":"<p><p>Cell communication systems based on polypeptide ligands use transmembrane receptors to transmit signals across the plasma membrane. In their biogenesis, receptors depend on the endoplasmic reticulum (ER)-Golgi system for folding, maturation, transport and localization to the cell surface. ER stress, caused by protein overproduction and misfolding, is a well-known pathology in neurodegeneration, cancer and numerous other diseases. How ER stress affects cell communication via transmembrane receptors is largely unknown. In disease models of multiple myeloma, chronic lymphocytic leukemia and osteogenesis imperfecta, we show that ER stress leads to loss of the mature transmembrane receptors FGFR3, ROR1, FGFR1, LRP6, FZD5 and PTH1R at the cell surface, resulting in impaired downstream signaling. This is caused by downregulation of receptor production and increased intracellular retention of immature receptor forms. Reduction of ER stress by treatment of cells with the chemical chaperone tauroursodeoxycholic acid or by expression of the chaperone protein BiP resulted in restoration of receptor maturation and signaling. We show a previously unappreciated pathological effect of ER stress; impaired cellular communication due to altered receptor processing. Our findings have implications for disease mechanisms related to ER stress and are particularly important when receptor-based pharmacological approaches are used for treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"209"},"PeriodicalIF":8.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059046","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}