Cell Death & Disease最新文献

{"title":"Single-cell analysis reveals that GFAP⁺ dedifferentiated Schwann cells promote tumor progress in PNI-positive distal cholangiocarcinoma via lactate/HMGB1 axis.","authors":"Ziyang Zu, Chong Zhang, Jianxiang Shi, Kunlun Chen, Hongwei Tang, Kaizhao Hu, Enchi Liu, Chengyang Ji, Ruo Feng, Xiaojing Shi, Wenlong Zhai","doi":"10.1038/s41419-025-07543-x","DOIUrl":"10.1038/s41419-025-07543-x","url":null,"abstract":"<p><p>Distal cholangiocarcinoma (dCCA) is a highly lethal malignancy that accounts for approximately 40% of patients with primary cholangiocarcinoma. Remarkable cellular heterogeneity and perineural invasion (PNI) are two typical features of dCCA. Deciphering the complex interplay between neoplastic and neural cells is crucial for understanding the mechanisms propelling PNI-positive dCCA progression. Herein, we conduct single-cell RNA sequencing on 24,715 cells from two pairs of PNI-positive dCCA tumors and adjacent tissues, identifying eight unique cell types. Malignant cells exhibit significant inter- and intra-tumor heterogeneity. We delineate the compositional and functional phenotypes of five Schwann cell (SC) subsets in PNI-positive dCCA. Moreover, our analyses reveal two potential cell subtypes critical to forming PNI: NEAT1⁺ malignant cells characterized by hypoxic propensity and GFAP⁺ dedifferentiated SCs featuring hypermetabolism. Further bioinformatics uncover extensive cellular interactions between these two subpopulations. Functional experiments confirm that lactate in the hypoxic tumor microenvironment can induce GFAP-dedifferentiation in SCs, which promotes cancer cell invasion and progression through upregulating HMGB1. Taken together, our findings offer a thorough characterization of the transcriptional profile in PNI-positive dCCA and unveil potential therapeutic targets for dCCA PNI.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"215"},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR-T therapy dilemma and innovative design strategies for next generation.","authors":"Zhiwei Wang, Peixian Li, Xiaoyu Zeng, Jing Guo, Cheng Zhang, Zusen Fan, Zhiwei Wang, Pingping Zhu, Zhenzhen Chen","doi":"10.1038/s41419-025-07454-x","DOIUrl":"10.1038/s41419-025-07454-x","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T-cell therapy has shown remarkable curative effects on hematological tumors, driving the exponential growth in CAR-T-related research. Although CD19-targeting CAR-T-cell therapy has displayed remarkable promise in clinical trials, many obstacles are arising that limit its therapeutic efficacy in tumor immunotherapy. The \"dilemma\" of CAR-T cell-based tumor therapy includes lethal cytotoxicity, restricted trafficking, limited tumor infiltration, an immunosuppressive microenvironment, immune resistance and limited potency. The solution to CAR-T-cell therapy's dilemma requires interdisciplinary strategies, including synthetic biology-based ON/OFF switch, bioinstructive scaffolds, nanomaterials, oncolytic viruses, CRISPR screening, intestinal microbiota and its metabolites. In this review, we will introduce and summarize these interdisciplinary-based innovative technologies for the next generation CAR-T-cell design and delivery to overcome the key barriers of current CAR-T cells.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"211"},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields).","authors":"Anat Klein-Goldberg, Tali Voloshin, Efrat Zemer Tov, Rom Paz, Lina Somri-Gannam, Alexandra Volodin, Lilach Koren, Lena Lifshitz, Aviv Meir, Ayelet Shabtay-Orbach, Roni Blatt, Shay Cahal, Catherine Tempel-Brami, Kerem Wainer-Katsir, Tal Kan, Bella Koltun, Boris Brant, Yiftah Barsheshet, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti","doi":"10.1038/s41419-025-07546-8","DOIUrl":"10.1038/s41419-025-07546-8","url":null,"abstract":"<p><p>Tumor Treating Fields (TTFields) are electric fields that induce cancer cell death. Genomic analysis of glioblastoma tumors resected from TTFields-treated patients suggested a potential link between a reduced or absent response to TTFields and activating mutations in the phosphatidylinositol 3-kinase (PI3K) p110α subunit (PIK3CA). Our study aimed to investigate the role of the PI3K/AKT pathway in the response to TTFields. We tested changes in signaling pathways in control versus TTFields-treated U-87 MG glioblastoma, A2780 ovarian carcinoma, and H1299 non-small cell lung cancer (NSCLC) cells using the Luminex multiplex assay, validated by western blot analysis and inhibition assays. We also performed in vivo validation using immunohistochemistry on tumor sections from animals bearing orthotopic N1-S1 hepatocellular, MOSE-L ovarian, or LL/2 lung tumors that were treated with TTFields or sham. Finally, we examined the efficacy of concomitant treatment with TTFields and PI3K inhibitors in cell lines and mouse models. Our findings elucidate the mechanisms driving PI3K/AKT activation following TTFields treatment, revealing that the AKT signaling amplitude increases over time and is influenced by cell-surface and cell-cell interactions. Specifically, focal adhesion kinase (FAK) and N-cadherin were found to promote AKT phosphorylation, activating cell survival pathways. Furthermore, our investigation revealed that pharmacological inhibition of PI3K sensitized cancer cells to TTFields, both in vitro and in vivo. Our research suggests that the PI3K/AKT pathway is involved in cancer cell response to TTFields, and that inhibition of this pathway may serve as a potential therapeutic target for sensitizing cancer cells to TTFields.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"210"},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.","authors":"Lucia Barazzuol, Tetiana Tykhonenko, Tia L Griffiths, Alessio Vagnoni, Marisa Brini, Tito Calì","doi":"10.1038/s41419-025-07511-5","DOIUrl":"10.1038/s41419-025-07511-5","url":null,"abstract":"<p><p>Organelle contact sites are crucial for cellular function, enabling the exchange of lipids, ions, and other molecules between different organelles. The ability to track these contact sites in vivo has been significantly advanced by the development of SPLICS (Split-GFP-based Contact Site Sensors) reporters, which have provided unprecedented insights into the intricate network of organelle communication. This innovative and powerful tool allows the real-time visualization of different organelle interactions in living cells and in vivo thus unraveling the complexity of their dynamic in the context of cellular homeostasis. Recent studies highlighted the dynamic nature of organelle contact sites either in terms of tethering/untethering and of movement of the contact itself in time and space: whether unique temporal behaviors and contact site-specific dynamics of different organelle interactions exist is currently unknown. In this study, we investigated the spatiotemporal distribution of various organelle contact sites using time-lapse in vitro and in vivo imaging and discovered an evolutionarily conserved dynamic pattern among different contact sites, influenced by the specific partner organelles involved. These findings highlight the importance of spatial and temporal regulation at organelle contact sites, which may underlie their diverse physiological functions. The discovery of contact site-specific dynamics opens new avenues for understanding the regulation of organelle interactions in health and disease, with potential implications for developing targeted therapeutic strategies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"214"},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Macrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis.","authors":"Qiong Wu, Zongwen Liang, Jing Jiang, Xiaoming Feng, Jinming Liu, Zongfeng Zhang, Honglin Wang, Ning Wang, Yanling Gou, Zhi Li, Yingying Cao","doi":"10.1038/s41419-025-07484-5","DOIUrl":"10.1038/s41419-025-07484-5","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"212"},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Expression of Concern: A novel 4-aminoquinazoline derivative, DHW-208, suppresses the growth of human breast cancer cells by targeting the PI3K/AKT/mTOR pathway.","authors":"Shu Wang, Yingshi Zhang, Tianshu Ren, Qiong Wu, Hongyuan Lu, Xiaochun Qin, Yuyan Liu, Huaiwei Ding, Qingchun Zhao","doi":"10.1038/s41419-025-07539-7","DOIUrl":"10.1038/s41419-025-07539-7","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"216"},"PeriodicalIF":8.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Ubiquitin-specific protease 25 ameliorates ulcerative colitis by regulating the degradation of phosphor-STAT3.","authors":"Zhengru Liu, Jian Liu, Yuping Wei, Jinting Li, Jixiang Zhang, Rong Yu, Qian Yang, Yinglei Miao, Weiguo Dong","doi":"10.1038/s41419-025-07491-6","DOIUrl":"10.1038/s41419-025-07491-6","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"207"},"PeriodicalIF":8.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin inhibits PD-L1 via ILF3 to induce ferroptosis in gastric cancer cells.","authors":"Danping Sun, Xiaohan Cui, Wenshuo Yang, Meng Wei, Zhibo Yan, Mingxiang Zhang, Wenbin Yu","doi":"10.1038/s41419-025-07562-8","DOIUrl":"10.1038/s41419-025-07562-8","url":null,"abstract":"<p><p>The treatment of gastric cancer remains challenging, with immunotherapy serving as a critical component of the holistic approach to its treatment. The results of this study indicated that statins could decrease the serum levels of interleukin-enhancing binding factor 3 (ILF3) and programmed cell death ligand 1(PD-L1) in GC patients and improve their prognosis. Functional experiments demonstrated that simvastatin induced ferroptosis by inhibiting ILF3 in GC cells and enhanced the killing effect of activated CD8⁺ T cells on GC cells. The CUT&Tag assay revealed that, mechanistically, simvastatin inhibited ILF3 expression by reducing the acetylation level at residue site H3K14 in ILF3. Next-generation sequencing and Kyoto Encyclopedia of Genes and Genomes analysis revealed that ILF3 regulated PD-L1 expression through the DEPTOR/mTOR signaling pathway. Overall, simvastatin induced ferroptosis in GC cells by inhibiting ILF3 expression while promoting the activation of CD8⁺ T cells to augment antitumor immune responses, thereby facilitating synergistic immunotherapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"208"},"PeriodicalIF":8.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRMT10A regulates tRNA-ArgCCT m¹G9 modification to generate tRNA-derived fragments influencing vasculogenic mimicry formation in glioblastoma.","authors":"Deng Wei, Bei Zhai, Hui Zeng, Long Liu, Han Gao, Shiqi Xiang, Xiaobai Liu, Jun Ma, Yang Lin, Yilong Yao, Ping Wang","doi":"10.1038/s41419-025-07548-6","DOIUrl":"10.1038/s41419-025-07548-6","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumor. The formation of vasculogenic mimicry (VM) in GBM is closely related to poor patient prognosis. Therefore, it is urgently necessary to explore the mechanisms that promote VM formation in GBM and identify therapeutic targets. CGGA data analysis revealed that TRMT10A expression is significantly downregulated in WHO grade IV primary glioma samples compared to grade II samples, consistent with the protein expression levels. Additionally, GBM patients with low TRMT10A expression have poorer prognoses. In human glioma cells, TRMT10A expression is significantly lower than in human astrocytes. Knockdown of TRMT10A reduces m¹G9 modification of tRNA-ArgCCT, upregulates tRF-22 expression, and promotes glioma cell proliferation, migration, invasion, and tube formation. Overexpression of tRF-22 in glioma cells significantly downregulates MXD1 expression. tRF-22 negatively regulates MXD1 expression by binding to its 3'UTR, reducing MXD1's transcriptional inhibition of HIF1A, thereby promoting glioma cell proliferation, migration, invasion, and tube formation. Overexpression of TRMT10A combined with tRF-22 inhibition significantly reduces the number of VM channels and inhibits tumor growth in xenograft models in nude mice. This study elucidates the mechanism by which TRMT10A affects VM formation in glioma and provides a novel therapeutic target for GBM.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"209"},"PeriodicalIF":8.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1.","authors":"Ning Sun, Sijia Wang, Jianting Liu, Peipei Zhang, Yixin Chang, Hongyan Li, Kun Zhao, Yijie Liu, Mingzhi Huang, Yan Hu, Zhenni Lin, Yongyong Lu, Guosong Jiang, Wei Chen, Chuanshu Huang, Honglei Jin","doi":"10.1038/s41419-025-07545-9","DOIUrl":"10.1038/s41419-025-07545-9","url":null,"abstract":"<p><p>X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m⁶A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 as its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced the expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of the MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"205"},"PeriodicalIF":8.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}