Cell Communication and Signaling最新文献

{"title":"Decoding the divide: what distinguishes apoptosis-induced proliferation from compensatory proliferation?","authors":"Andreas Bergmann, Yun Fan","doi":"10.1186/s12964-025-02336-3","DOIUrl":"10.1186/s12964-025-02336-3","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"334"},"PeriodicalIF":8.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610366","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 novel MIR100HG transcript enhances tumorigenesis by inducing BCLAF1-mediated alternative splicing in colorectal cancer.","authors":"Mingrui Dai, Yuhua Shi, Hailin Zhao, Yue Hu, Xianling Cong, Bin Yu, Haihong Zhang, Xianghui Yu, Hui Wu","doi":"10.1186/s12964-025-02280-2","DOIUrl":"10.1186/s12964-025-02280-2","url":null,"abstract":"<p><strong>Background: </strong>Long non-coding RNAs (lncRNAs) play crucial roles in cancer pathogenesis, including colorectal cancer (CRC). Distinct lncRNA transcripts from the same gene show diverse regulatory roles in cancer. The MIR100HG, a lncRNA gene characterized by multiple transcript variants, has been implicated in promoting CRC oncogenesis. However, the specific functions of individual MIR100HG transcripts in tumorigenesis remain unclear.</p><p><strong>Methods: </strong>We explored the MIR100HG transcripts upregulated by TGFβ1 treated in CRC cells using RNA-Seq and characterized a novel transcript in CRC cells and tumor tissues via qRT-PCR. Chromatin immunoprecipitation and luciferase assays revealed this transcript's upstream regulation. Functional experiments were performed in vitro and in mouse models. The molecular mechanism was elucidated through RNA-seq, RNA pull-down, mass spectrometry, RNA immunoprecipitation and co-immunoprecipitation. Finally, we evaluated the transcript's therapeutic potential by treating mouse model tumors with antisense oligonucleotide.</p><p><strong>Results: </strong>We identified a novel transcript, MIR100HG-L, which retains more portion of exon 1 compared to the previously reported shorter transcript. MIR100HG-L was transcriptionally upregulated by TGFβ/SMAD signaling and exhibited elevated expression in CRC tissues. Functionally, this transcript was demonstrated to promote CRC cell proliferation, suppress apoptosis and enhance drug resistance. Mechanistically, MIR100HG-L specifically interacted with BCLAF1, serving as a protein scaffold to connect BCLAF1 with splicing factors. This interaction significantly induced BCLAF1-mediated splicing events of oncogenes related to apoptosis and DNA damage response, enhancing their expression and contributing to CRC development. MIR100HG-L-targeted antisense therapy reduced tumor growth and increased cetuximab sensitivity.</p><p><strong>Conclusions: </strong>Our study reveals a novel MIR100HG transcript induced by TGFβ/SMAD signaling and explores its distinct oncogenic mechanism through a structure-specific interaction with the BCLAF1. These findings suggest distinct MIR100HG transcripts may exert diverse functions and lead to the identification of novel molecular markers and therapeutic targets for CRC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"328"},"PeriodicalIF":8.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602305","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":"Artificial intelligence-driven discovery of YH395A: A novel TGFβR1 inhibitor with potent anti-tumor activity against triple-negative breast cancer.","authors":"Jun Ling, Jie Zhang, Baozhen Wang, Jing FengSong, Tao Li, Jing Chen","doi":"10.1186/s12964-025-02337-2","DOIUrl":"10.1186/s12964-025-02337-2","url":null,"abstract":"<p><p>Characterized by high malignancy and limited treatment efficacy, triple-negative breast cancer (TNBC) remains a clinically challenging subtype within breast cancer classifications, marked by rapid progression and high mortality. Abnormal activation of the transforming growth factor-β (TGFβ) pathway signaling, a pathway integral to tumor progression, metastasis, angiogenesis and immune evasion, is a common feature in a broad spectrum of malignancies. Owing to the restricted effectiveness of first-line interventions including surgical resection, cytotoxic agents, and radiation therapy for TNBC, novel agents that modulate TGFβ activity represent a compelling therapeutic avenue. Herein, we reported the identification and preclinical evaluation of YH395A, a novel tetrahydro-β-carboline derivative derived from the lead compound YR-290 with virtual screening from pseudo molecular library generated by generative deep learning method. In vitro studies demonstrated that YH395A dose-dependently inhibited TNBC cell migration and invasion. In vivo, administration of YH395A not only curtailed metastatic dissemination and prevented the extravasation of breast cancer cells into lung parenchyma in mouse models but also significantly reduced tumor growth in a patient-derived xenograft (PDX) model. Mechanistic analyses indicated that these antitumor effects are mediated via potent inhibition of TGFβ signaling. These cumulative results demonstrate YH395A's viability as a novel therapeutic agent for TNBC, while emphasizing the necessity for expanded preclinical validation studies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"326"},"PeriodicalIF":8.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592983","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":"JC124 confers multimodal neuroprotection in epilepsy by suppressing NLRP3 inflammasome activation: evidence from animal and human neuronal models.","authors":"Peng Zhang, Zhipeng Li, Minxue Liang, Jinxian Yuan, Jinyu Zhou, Jie Zhang, Jing Deng, Yalan Chen, Hao Tang, Chengjie Xu, Chenjun Shi, Limin Ma, Qiankun Liu, Yong Liu, Yangmei Chen, Hui Zhang","doi":"10.1186/s12964-025-02239-3","DOIUrl":"10.1186/s12964-025-02239-3","url":null,"abstract":"<p><strong>Background: </strong>Despite continuous development of antiseizure medications (ASMs), global seizure control rates remain unsatisfactory, highlighting the urgent need for novel ASMs targeting distinct pathophysiological mechanisms. Inhibition of NLRP3 inflammasome activation represents an emerging strategy to simultaneously attenuate seizures and associated neuropsychiatric comorbidities. Therefore, this study investigates whether JC124, a novel NLRP3 inflammasome inhibitor, exerts neuroprotective effects in kainic acid (KA)-induced epileptic mice and in human induced pluripotent stem cell (hiPSC)-derived neurons stimulated by lipopolysaccharide (LPS) and adenosine triphosphate (ATP).</p><p><strong>Methods: </strong>Summary-based Mendelian Randomization (SMR) was used to analyze the association between NLRP3 alleles and epilepsy susceptibility. NLRP3 knockout mice were generated, and then epileptic mice induced by intrahippocampal KA injection were administered JC124 (50 mg/kg, intraperitoneal) once daily for 28 days. The spontaneous recurrent seizures, hippocampal local field potential, depressive-like behavior, cognitive dysfunction, and locomotor ability of mice were evaluated. The brain tissues of the mice were collected for Western blotting, immunohistochemistry, immunofluorescence labeling, enzyme-linked immunosorbent assay, transmission electron microscopy, and morphological staining. The binding capacity of JC124 to the human NLRP3 protein was assessed using molecular docking and molecular dynamics simulations. hiPSC-derived neurons were used to explore the neuroprotective effects of JC124 against inflammatory injury in human neurons.</p><p><strong>Results: </strong>In this study, a positive correlation was identified between the expression of the NLRP3 gene and the susceptibility to epilepsy through SMR analysis. JC124 intervention markedly inhibited seizures and improved depressive-like behavior and cognitive dysfunction. It also reduced hippocampal neuronal loss, neuronal pyroptosis, microgliosis, and astrogliosis. Importantly, the neuroprotective effects of JC124 in KA-induced epileptic mice were mediated through the inhibition of the NLRP3 inflammasome. JC124 inhibited neuroinflammation and oxidative stress in KA-treated NLRP3 wild-type mice, but not in KA-treated NLRP3 knockout mice. Furthermore, JC124 bound directly to the human NLRP3 protein and alleviated neuroinflammation and oxidative stress in hiPSC-derived neurons stimulated by LPS and ATP.</p><p><strong>Conclusions: </strong>These findings indicate that inhibiting the activation of the NLRP3 inflammasome with JC124 represents a potentially safe and innovative therapeutic strategy to mitigate neuroinflammation and oxidative stress in epilepsy and to alleviate seizures and associated neuropsychiatric comorbidities.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"327"},"PeriodicalIF":8.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592984","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 scaffold protein DLG4 facilitates RNF63-mediated ubiquitination and degradation of STAT3 in non-small cell lung cancer.","authors":"Shisong Chen, Hongjie Xu, Ning Li, Yang Yang, Ruxi Pang, Shuwei Zhang, Junjie Qiao, Hao Chen","doi":"10.1186/s12964-025-02334-5","DOIUrl":"10.1186/s12964-025-02334-5","url":null,"abstract":"<p><strong>Background: </strong>The Disks-large homolog (DLG) family has been found to govern multiple key processes in human cancers. However, their role in non-small cell lung cancer (NSCLC) remains unknown.</p><p><strong>Methods: </strong>The expression of DLG4 was determined by immunoblotting and q-PCR. The interacting proteins of DLG4 were identified by affinity purification mass spectrometry. The ubiquitination level of STAT3 was verified by denaturation-IP. The protein interactions were determined by co-IP. The clinical significance of DLG4, RNF63, and STAT3 was evaluated by immunohistochemical staining.</p><p><strong>Results: </strong>In this study, by evaluating the expression levels of human DLG protein (DLG1-DLG5), we found that DLG4 is significantly downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), two major types of NSCLC. DLG4 overexpression impairs cell proliferation and epithelial-mesenchymal transition migration (EMT) of NSCLC cells. The xenograft model also verifies the inhibitory effects of DLG4 on tumor growth in vivo. Moreover, we determined that DLG4 functions as a novel regulator of STAT3. Mechanistically, DLG4 directly interacts with STAT3 and recruits E3 ubiquitin ligase RNF63 (MKRN3) to STAT3, which promotes STAT3 K48-linked polyubiquitination and proteasome-mediated degradation. Importantly, in human NSCLC specimens, endogenous DLG4 and RNF63 expression levels are inversely correlated with that of STAT3. Moreover, low DLG4 and RNF63 expression correlates with poor patient survival in NSCLC.</p><p><strong>Conclusion: </strong>our findings define the role of DLG4 that can diminish NSCLC cell proliferation and tumorigenesis through degrading STAT3 in an RNF63-dependent manner. This work suggests a new treatment strategy against NSCLC caused by aberrant activation of STAT3.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"325"},"PeriodicalIF":8.2,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576934","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":"Enhanced immunotherapy response in lung adenocarcinoma patients with COPD: insights into tumor cells and immune microenvironment characteristics.","authors":"Yuji Huang, Boxuan Liang, Xuewei Chen, Zhiming Li, Yanhong Deng, Jiaxin Du, Yizhou Zhong, Xi Lin, Junjun Fu, Jieyu Xie, Xin Zhang, Zhenlie Huang","doi":"10.1186/s12964-025-02332-7","DOIUrl":"10.1186/s12964-025-02332-7","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"324"},"PeriodicalIF":8.2,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565523","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":"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220258/pdf/","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":"OA","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}