Cell Communication and Signaling最新文献

{"title":"GPX3 promotes cisplatin resistance in TNBC by manipulating ROS-TGFB1-ZEB2.","authors":"Qingyi Hu, Qianzhi Chen, Wen Yang, Anwen Ren, Jie Tan, Tao Huang","doi":"10.1186/s12964-025-02356-z","DOIUrl":"10.1186/s12964-025-02356-z","url":null,"abstract":"<p><strong>Background: </strong>Due to the lack of effective targeted therapies and the high likelihood of acquired resistance, triple-negative breast cancer (TNBC) remains one of the deadliest cancers affecting women globally. Investigating the mechanism underlying TNBC's resistance to platinum-based chemotherapy and identifying new therapeutic targets are urgent priorities.</p><p><strong>Methods: </strong>The expression level of GPX3, cisplatin sensitivity, and ROS production were compared across three TNBC cell lines to elucidate the relationship between GPX3 and platinum resistance. RNA sequencing and bioinformatics analyses of GPX3 knockdown cells revealed its regulation of stress-related signaling pathways and TGFB1. The regulation of TGFB1 by GPX3 was further investigated using Western blotting, RNA interference, confocal microscopy, and inhibitor treatments. The correlation between the expression level of GPX3, TGFB1, and ZEB2 was analyzed using breast cancer microarrays and the TCGA database. The effect of GPX3 on platinum sensitivity in TNBC was studied using a mouse xenograft model.</p><p><strong>Results: </strong>GPX3 expression was upregulated in more invasive TNBC cells, promoting resistance to cisplatin-based chemotherapy. RNA sequencing revealed that the deletion of GPX3 resulted in a decrease in gene expression patterns associated with pro-tumor signaling pathways. Validation experiments confirmed that the upregulation of TGFB1 in acquired cisplatin resistance is highly dependent on GPX3. Further investigation revealed that the TGFB1-ZEB2 axis mediated platinum resistance and metastasis through epithelial-mesenchymal transition (EMT). Additionally, platinum treatment increased GPX3 and TGFB1 expression and secretion, and their depletion enhanced platinum sensitivity in TNBC cells. We identified the GPX3-TGFB1-ZEB2 regulatory axis and found a positive correlation in the expression of all three in clinical samples. Our study also demonstrated that GPX3 knockdown inhibited TNBC tumor growth in platinum-treated mouse models.</p><p><strong>Conclusions: </strong>This study reveals the signaling pathway mediated by GPX3-TGFB1-ZEB2 and its role in acquired platinum resistance and EMT in TNBC. Our findings suggest that GPX3 is a promising biomarker and potential therapeutic target for the diagnosis, treatment, and prognosis of high-risk TNBC patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"355"},"PeriodicalIF":8.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719188","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":"ACACA depletion activates the cPLA2-arachidonic acid-NF-κB axis to drive inflammatory reprogramming in androgen receptor-independent prostate cancer.","authors":"Shaoyou Liu, Yupeng Chen, Jian Chen, Jinchuang Li, Zhenguo Liang, Xinyue Mei, Yuanfa Feng, Zhaodong Han, Funeng Jiang, Yongding Wu, Huijing Tan, Hongwei Luo, Huichan He, Jiarun Lai, Weide Zhong","doi":"10.1186/s12964-025-02363-0","DOIUrl":"10.1186/s12964-025-02363-0","url":null,"abstract":"<p><strong>Background: </strong>Acetyl-CoA carboxylase alpha (ACACA) is a key enzyme in fatty acid biosynthesis and a proposed therapeutic target in prostate cancer. However, its role in androgen receptor-independent prostate cancer (ARIPC), an aggressive and treatment-resistant subtype, remains unclear. This study aimed to investigate the effects of ACACA depletion on ARIPC, with a focus on inflammation and metastasis.</p><p><strong>Methods: </strong>ACACA expression patterns were analyzed across multiple metastatic castration-resistant prostate cancer (mCRPC) datasets. In ARIPC cell lines, ACACA was inhibited via both shRNA and the pharmacological inhibitor TOFA. Transcriptomic, metabolomic, and single-cell RNA sequencing data were used to identify downstream changes. Inflammatory signaling was assessed by qPCR, western blotting, and immunofluorescence. Cell migration was evaluated via wound healing and transwell assays, and the metastatic potential was examined in a mouse tail vein injection model. The roles of arachidonic acid (AA), cytosolic phospholipase A2 (cPLA2), and NF-κB signaling were further tested through targeted inhibition.</p><p><strong>Results: </strong>ACACA expression was reduced in ARIPC and was negatively correlated with inflammatory pathways. Its inhibition upregulated proinflammatory cytokines and chemokines, elevated AA and eicosanoid levels, and increased cPLA2 expression. Single-cell RNA sequencing confirmed NF-κB signaling enrichment in ACACA-low tumor cells. Mechanistically, elevated AA activated NF-κB signaling. ACACA depletion enhanced cell migration and metastasis, along with macrophage infiltration. Inhibiting cPLA2 or NF-κB signaling reversed these effects.</p><p><strong>Conclusions: </strong>This study reveals a previously unrecognized tumor-promoting effect of ACACA depletion in ARIPC. Targeting ACACA in this context enhances inflammation and metastasis via arachidonic acid-mediated activation of NF-κB signaling. These findings highlight a context dependent, tumor-promoting role of ACACA inhibition and underscore the need for combinational strategies to avoid potential adverse outcomes in metabolic therapies.</p><p><strong>Trial registration: </strong>Not applicable.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"352"},"PeriodicalIF":8.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719187","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":"Silencing P2Y₁₂ and P2Y₁₃ receptors rehabilitates the ADP-induced P2Y₁-mediated osteogenic commitment of post-menopausal mesenchymal stromal cells.","authors":"Catarina Bessa-Andrês, Rui Pinto-Cardoso, Maria Adelina Costa, Fátima Ferreirinha, José Marinhas, Rolando Freitas, Rui Lemos, Diogo Catelas, Adélio Vilaça, António Oliveira, Paulo Correia-de-Sá, José Bernardo Noronha-Matos","doi":"10.1186/s12964-025-02355-0","DOIUrl":"10.1186/s12964-025-02355-0","url":null,"abstract":"<p><strong>Background: </strong>Participation of ADP-sensitive metabotropic P2Y₁, P2Y₁₂ and P2Y₁₃ receptors in human osteogenesis is controversial. Here, we investigated the variations in the expression and bone-forming properties of the P2Y₁R in osteogenic-differentiating bone marrow-derived mesenchymal stromal cells (BM-MSCs) isolated from post-menopausal (Pm) women. We also tested whether observed P2Y₁-related functional deficits result from the crosstalk with co-localized P2Y₁₂ and P2Y₁₃ receptors.</p><p><strong>Methods: </strong>Pm BM-MSCs were cultured in an osteogenic-inducing medium in either the absence or presence of the selective P2Y₁ receptor agonist, MR2365; this compound was applied alone or after cells' incubation with selective P2Y₁₂ and P2Y₁₃ receptor antagonists or short hairpin RNAs designed to silence P2Y₁₂ or P2Y₁₃ receptors gene expression.</p><p><strong>Results: </strong>BM-MSCs present immunoreactivity against all ADP-sensitive P2Y receptor subtypes, but their relative density varied among different Pm women and with the time of the cells in the culture. The P2Y₁receptor agonist increased the alkaline phosphatase activity and bone nodule formation in BM-MSCs originating from a younger female, but it failed to promote the osteogenic differentiation of BM-MSCs from Pm women unless P2Y₁₂ or P2Y₁₃ receptors are blocked with AR-C66096 and MRS211, respectively. Silencing the P2Y₁₃, but not the P2Y₁₂, receptor gene expression restored the P2Y₁-mediated osteogenic commitment of Pm BM-MSCs. The P2Y₁ receptor agonist failed to elicit [Ca²⁺]_i transients inside Pm BM-MSCs except after acute cholesterol depletion and lipid rafts disruption with methyl-β-cyclodextrin to prevent the P2Y₁/P2Y₁₃ receptors interplay.</p><p><strong>Conclusions: </strong>Thus, personalized offsetting the activity and/or expression of P2Y₁₃ receptor (and P2Y₁₂) may be a good strategy to rehabilitate the P2Y₁-mediated osteogenic potential of BM-MSCs and to reduce the fracture risk in Pm women.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"353"},"PeriodicalIF":8.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719191","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":"Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity.","authors":"Uğur Kahya, Vasyl Lukiyanchuk, Ielizaveta Gorodetska, Matthias M Weigel, Ayşe Sedef Köseer, Berke Alkan, Dragana Savic, Annett Linge, Steffen Löck, Mirko Peitzsch, Ira-Ida Skvortsova, Mechthild Krause, Anna Dubrovska","doi":"10.1186/s12964-025-02344-3","DOIUrl":"10.1186/s12964-025-02344-3","url":null,"abstract":"<p><strong>Background: </strong>Metabolic and stress response adaptations in prostate cancer (PCa) mediate tumor resistance to radiation therapy (RT). Our study investigated the roles of glutamine (Gln) transporters SLC1A5, SLC7A5, and SLC38A1 in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT.</p><p><strong>Methods: </strong>The radiosensitizing potential of GLS inhibition with CB-839 was analyzed in prostate cancer xenograft models. The level of gene expression was analyzed by RNA sequencing and RT-qPCR in the established cell lines or patient-derived tumor and adjacent non-cancerous tissues. Phosphoproteomic analysis was employed to identify the underlying signaling pathways. The publicly available PCa patient datasets, and a dataset for the patients treated with RT were analyzed by SUMO software. The key parameters of mitochondrial functions were measured by Seahorse analysis. Analysis of the general oxidative stress level and mitochondrial superoxide detection were conducted using flow cytometry. γH2A.X foci analysis was used to assess the DNA double strand break. Relative cell sensitivity to RT was evaluated by radiobiological clonogenic assays. Aldefluor assay and sphere-forming analysis were used to determine cancer stem cell (CSC) phenotype.</p><p><strong>Results: </strong>A siRNA-mediated knockdown of Gln transporters SLC1A5, SLC7A5, and SLC38A1 resulted in significant radiosensitization of PCa cells. Consistently, the first-in-clinic glutaminase (GLS) inhibitor CB-839, combined with RT, demonstrated a synergistic effect with radiotherapy in vivo, significantly delaying tumor growth. Inhibition of Gln metabolism or knockdown of Gln transporters SLC1A5, SLC7A5, or SLC38A1 induces expression of NUPR1, a stress response transcriptional regulator, but simultaneously uncouples the NUPR1-driven metabolic stress-adaptation program. Similarly to the effect from NUPR1 knockdown, depletion of these Gln transporters led to reduced cell viability, accumulation of mitochondrial ROS, and increased PCa radiosensitivity. This effect is more pronounced in PCa cells with high dependency on OXPHOS for energy production.</p><p><strong>Conclusions: </strong>Our work underscores the role of Gln transporters and the NUPR1-mediated stress response in PCa cell survival, oxidative stress, mitochondrial functions, and radioresistance. Our findings provide a potential therapeutic in vivo strategy to enhance the efficacy of RT and suggest a potential synergism between the depletion of Gln transporters or NUPR1 and OXPHOS inhibition.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"351"},"PeriodicalIF":8.2,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709988","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":"Long interspersed nuclear element 1 methylation in non-small cell lung cancer: implications for diagnosis, prognosis, and therapeutic targeting.","authors":"Dileesha Prabani Wanasundara Arachchillage, Wanvisa Udomsinprasert","doi":"10.1186/s12964-025-02343-4","DOIUrl":"10.1186/s12964-025-02343-4","url":null,"abstract":"<p><p>Long interspersed nucleotide element 1 (LINE1), the most abundant repetitive element in the human genome, plays a crucial role in genomic instability. Aberrant LINE1 activation, primarily regulated by DNA methylation, is a hallmark of cancer. Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer worldwide, continues to pose significant challenges due to the invasiveness, high cost, and susceptibility to false positives of current diagnostic methods, as well as the emergence of treatment resistance. This review highlights the potential of LINE1 methylation as a biomarker for NSCLC, offering novel insights into its role in diagnosis, prognosis, and therapeutic strategies. Recent studies uncovered that LINE1 hypomethylation was strongly associated with poor overall survival, suggesting its utility as both a prognostic marker and a therapeutic target. However, further research is required to elucidate its precise regulatory mechanisms in LINE1 retrotransposition and to evaluate its potential as a non-invasive biomarker for improving NSCLC management.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"350"},"PeriodicalIF":8.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692528","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":"HAX1 inhibits apoptosis and promotes maturation of neutrophils.","authors":"Hanwei Yue, Guiying Shi, Jiaming Tang, Xinyue Li, Lin Bai","doi":"10.1186/s12964-025-02353-2","DOIUrl":"10.1186/s12964-025-02353-2","url":null,"abstract":"<p><p>As the diverse functions of neutrophils continue to be uncovered, elucidating the molecular mechanisms that regulate their differentiation, development, and apoptosis has become crucial for overcoming limitations in the treatment of neutrophil-related diseases. Hematopoietic cell-specific protein 1-associated protein X 1 (HAX1), encoded by the primary pathogenic gene of autosomal recessive severe congenital neutropenia, serves as a key target for in-depth exploration of neutrophil function. In the Hax1 myeloid knockout C57BL/6J mice and stably transduced HL-60 cells with HAX1 knockdown that we constructed, our results showed that the differentiation of granulocyte-monocyte precursor cells (GMPs) and the maturation of neutrophils were inhibited, significantly reducing the proportion of myeloid cells and neutrophils in both bone marrow and peripheral blood. In addition, HAX1 deletion disrupted mitochondrial structure and mitochondrial membrane potential in neutrophils and increased the protein levels of B-cell lymphoma 2 (BCL-2) family members and cleaved Caspase-9. Through RNA sequencing and mRNA validation, we further demonstrated that HAX1 regulates neutrophil apoptosis and maturation via the mitochondrial-mediated classical apoptotic pathway and toll-like receptor 2 (TLR2)-mediated purine-rich box 1 (PU.1) signaling. This study elucidated the critical role of HAX1 in neutrophil differentiation, maturation, and apoptosis, providing new targets for research into neutrophil-related diseases.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"349"},"PeriodicalIF":8.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683632","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":"NAMPT and NNMT released via extracellular vesicles and as soluble mediators are distinguished traits of BRAF inhibitor resistance of melanoma cells impacting on the tumor microenvironment.","authors":"Beatrice Ghezzi, Irene Fiorilla, Ágata Carreira, Francesco Recco, Leonardo Sorci, Lidia Avalle, Alessia Ponzano, Francesca Mazzola, Alberto Maria Todesco, Nicoletta Tommasi, Massimiliano Gasparrini, Vito Giuseppe D'Agostino, Flavio Mignone, Alessandro Provenzani, Valentina Audrito","doi":"10.1186/s12964-025-02361-2","DOIUrl":"10.1186/s12964-025-02361-2","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"348"},"PeriodicalIF":8.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683633","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":"MIR4726^EccDNA drives bortezomib resistance in multiple myeloma by enhancing MIR4726-5p/NXF1/NKIRAS2 axis dependent autophagy.","authors":"Fangfang Li, Xinyi Long, Sishi Tang, Jinhua Yan, Jing Liu, Yunfeng Fu","doi":"10.1186/s12964-025-02340-7","DOIUrl":"10.1186/s12964-025-02340-7","url":null,"abstract":"<p><strong>Background: </strong>Despite many new drugs, multiple myeloma (MM) remains an incurable plasma cell malignancy, and drug resistance is a long-standing topic in this field. Characterized by efficient transcription without being limited by the double helix structure and promoter, extrachromosomal circular DNA (EccDNA) has been proven to be widely involved in cancer development and drug resistance.</p><p><strong>Methods: </strong>We performed circle-seq and mRNA-seq on samples from three MM patients at the time of complete response and relapse to screen EccDNA candidate molecules. Outward PCR and Sanger sequencing were used to identify EccDNA molecules. RT‒qPCR and WB were performed to detect gene expression levels. Fluorescence in situ hybridization (FISH) was carried out to detect the deletion of chromosome 17p (del (17p)). Transmission electron microscopy (TEM) was conducted to observe autophagosomes. Luciferase reporter assays were performed to validate the binding of microRNAs to target genes. Cell viability assays and apoptosis assays were employed to assess drug resistance. Xenograft tumor mouse models were established for in vivo experiments. Immunohistochemistry (IHC) was used to detect protein expression levels.</p><p><strong>Results: </strong>We successfully identified an EccDNA molecule (EccDNA^{chr17:38719676-38719812}) in one relapsed MM patient with del(17p) and named it MIR4726^EccDNA. We demonstrated that the overexpression of MIR4726^EccDNA in MM cells can increase bortezomib resistance. We further confirmed that the precursor miRNA carried by MIR4726^EccDNA can be efficiently transcribed in MM cells and that MIR4726^EccDNA drives bortezomib resistance via the MIR4726-5p/NXF1/NKIRAS2 axis. We further revealed that downregulation of NFKB inhibitor interacting Ras like 2 (NKIRAS2) activated the NF-κB pathway and increased autophagy. Moreover, we established a xenograft model of human MM via subcutaneous inoculation. We administered intra-tumoral injection of AgoMIR4726-5p and intraperitoneal injection of bortezomib and found that AgoMIR4726-5p promoted tumor progression and partially drove bortezomib resistance.</p><p><strong>Conclusions: </strong>In summary, our findings indicate that artificially synthesized MIR4726^EccDNA is functional in cells and that MIR4726^EccDNA enhances tumor progression and partially mediates drug resistance by enhancing MIR4726-5p/NXF1/NKIRAS2 axis dependent autophagy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"346"},"PeriodicalIF":8.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668979","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 gut-heart axis: a correlation between Paneth cells' dysfunction, microbiome dysbiosis, and cardiovascular diseases.","authors":"Aysa Rezabakhsh, Solomon Habtemariam, Rezayat Parvizi, Anne Meddahi-Pellé, Violeta Rodriguez Ruiz, Graciela Pavon-Djavid, Abolfazl Barzgari","doi":"10.1186/s12964-025-02335-4","DOIUrl":"10.1186/s12964-025-02335-4","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"347"},"PeriodicalIF":8.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668980","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":"Dexamethasone induces transgenerational inheritance of fetal-derived glomerulosclerosis phenotype in offspring through GR/DNMT3a mediated alterations of the lncRNA-Meg3/Notch signaling pathway.","authors":"Xiaoqi Zhao, Zhaojun Wang, Zhiping Xia, Haiyun Chen, Yanan Zhu, Songdi Wang, Yan Bao, Yutang Liu, Hui Wang, Ying Ao","doi":"10.1186/s12964-025-02346-1","DOIUrl":"10.1186/s12964-025-02346-1","url":null,"abstract":"<p><p>Prenatal dexamethasone exposure (PDE) has been reported to be associated with negative pregnancy outcomes and increased susceptibility to chronic diseases in their offspring. This study aimed to explore the transgenerational effects and mechanisms of renal developmental toxicity in offspring induced by PDE. We found that PDE caused fetal renal dysplasia and adult glomerulosclerosis phenotype in F1-F3 female offspring. Sequencing and experimental assays revealed that PDE reduced DNA methylation levels in the promoter region of the imprinted gene lncRNA Meg3 (Meg3), increased the expression of Meg3 and reduced the expression of the downstream Notch signaling pathway in kidneys of F1-F3 female fetuses. Meanwhile, Meg3 expression was increased in oocytes of PDE F1 and F2 offspring. The results of the in vitro experiments confirmed that dexamethasone activates GR and reduces DNMT3a expression in primary metanephric mesenchymal stem cells (MMSCs), which causes Meg3 hypomethylation/hyperexpression and the inhibition of the Notch signaling pathway, resulting in fetal renal dysplasia. Knockdown of GR expression, overexpression of DNMT3a, or silencing of Meg3 could reverse the downstream-associated alterations. In summary, PDE induced fetal-derived glomerulosclerosis phenotype mediated by the GR/DNMT3a/Meg3/Notch signal pathway in fetal rats, which had transgenerational inheritance effects and may be associated with increased Meg3 expression transmitted via oocytes. This study confirmed the transgenerational inheritance of fetal-derived glomerulosclerosis phenotype induced by PDE and provided an experimental basis for investigating the underlying mechanisms.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"345"},"PeriodicalIF":8.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661038","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}