Cell Death and Differentiation最新文献

{"title":"KDM3A controls postnatal hippocampal neurogenesis via dual regulation of the Wnt/β-catenin signaling pathway","authors":"Kin Pong U, Lin Gao, Huan Zhang, Zeyuan Ji, Jiacheng Lin, Shenyi Peng, Xiaohu Zhang, Shaolong Xue, Weifeng Qin, Lai Ling Tsang, Yonglun Kong, Yin Xia, Patrick Ming-Kuen Tang, Tao Wang, Wayne Yuk Wai Lee, Gang Li, Xiaohua Jiang","doi":"10.1038/s41418-025-01470-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01470-2","url":null,"abstract":"<p>Hippocampal neurogenesis, the generation of new neurons in the dentate gyrus (DG) of mammalian hippocampus, is essential for cognitive and emotional processes. Despite advances in understanding the transcription factors and signaling pathways that regulate DG neurogenesis, the epigenetic mechanisms underlying the molecular changes necessary for granule neuron generation remain poorly understood. In this study, we investigate the role of the H3K9 demethylase KDM3A in postnatal neurogenesis in mouse DG. Using <i>Kdm3a</i>-tdTomato reporter mice, we demonstrate that KDM3A is predominantly expressed in neural stem/progenitor cells (NSPCs) during postnatal DG development. Conventional or conditional knockout (cKO) of <i>Kdm3a</i> in NSPCs hinders postnatal neurogenesis, compromising learning and memory abilities and impairing brain injury repair in mice. Loss of KDM3A in NSPCs suppresses proliferation and neuronal differentiation while promoting glial differentiation in vitro. KDM3A localizes both in the nucleus and cytoplasm of NSPCs and regulates the Wnt/β-catenin signaling pathway through dual mechanisms. Firstly, KDM3A modulates the transcription of Wnt targets and a set of neurogenesis-related genes through its histone demethylase activity. Secondly, in the cytoplasm, KDM3A interacts with casein kinase I alpha (CK1α), regulating its ubiquitination. Loss of KDM3A enhances CK1α stability, leading to increased phosphorylation and degradation of β-catenin. Finally, quercetin, a geroprotective small molecule, upregulates KDM3A protein expression and promotes adult hippocampal neurogenesis following brain injury. However, these effects are diminished in <i>Kdm3a</i> KO mice, indicating that quercetin primarily promotes hippocampal neurogenesis through the regulation of KDM3A. In conclusion, our study highlights KDM3A as a crucial regulator of postnatal hippocampal neurogenesis, influencing NSPC proliferation and differentiation via the Wnt/β-catenin signaling pathway. These findings have potential implications for the development of new therapeutic approaches for neurological disorders and injuries.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"32 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-1β drives SARS-CoV-2-induced disease independently of the inflammasome and pyroptosis signalling","authors":"Stefanie M. Bader, Lena Scherer, Jan Schaefer, James P. Cooney, Liana Mackiewicz, Merle Dayton, Smitha Rose Georgy, Kathryn C. Davidson, Cody C. Allison, Marco J. Herold, Andreas Strasser, Marc Pellegrini, Marcel Doerflinger","doi":"10.1038/s41418-025-01459-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01459-x","url":null,"abstract":"<p>Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Certain programmed cell death processes can drive inflammation, however, their role in the pathogenesis of severe COVID-19 is unclear. Pyroptosis is a pro-inflammatory form of regulated cell death initiated by inflammasomes and executed by the pore-forming protein gasdermin D (GSDMD). Using an established mouse adapted SARS-CoV-2 virus and a panel of gene-targeted mice we found that deletion of the inflammasome (NLRP1/3 and the adaptor ASC) and pore forming proteins involved in pyroptosis (GSDMA/C/D/E) only marginally reduced IL-1β levels and did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. Finally, we did not observe any difference between WT animals and mice with compound deficiencies in the pro-inflammatory initiator caspases (<i>C1/11/12</i>^{<i>−/−</i>}). This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate pro-IL-1β, pro-IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1β, but not the absence of IL-18, ameliorated disease and enhanced survival in SARS-CoV-2 infected animals compared to wildtype mice. Collectively, these findings demonstrate that IL-1β is an important factor contributing to severe SARS-CoV-2 disease, but its release was largely independent of inflammasome and pyroptotic pathways.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Trim32-DPEP2 axis is an inflammatory switch in macrophages during intestinal inflammation","authors":"Zhiyan Zhan, Huisheng Liang, Zhuoqi Zhao, Liya Pan, Jing Li, Yuyun Chen, Zhoulonglong Xie, Zhilong Yan, Ying Xiang, Wenxue Liu, Li Hong","doi":"10.1038/s41418-025-01468-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01468-w","url":null,"abstract":"<p>The mechanisms via which inflammatory macrophages mediate intestinal inflammation are not completely understood. Herein, using merged analysis of RNA sequencing and mass spectrometry-based quantitative proteomics, we detected differences between proteomic and transcriptomic data in activated macrophages. Dipeptidase-2 (DPEP2), a member of the DPEP family, was highly expressed and then downregulated sharply at the protein level but not at the mRNA level in macrophages in response to inflammatory stimulation. Suppression of DPEP2 not only enhanced macrophage-mediated intestinal inflammation in vivo but also promoted the transduction of inflammatory pathways in macrophages in vitro. Mechanistically, overexpressed DPEP2 inhibited the transduction of inflammatory signals by resisting MAK3K7 in inactivated macrophages, whereas DPEP2 degradation by activated Trim32 resulted in strong activation of NF-κB and p38 MAPK signaling via the release of MAK3K7 in proinflammatory macrophages during the development of intestinal inflammation. The Trim32-DPEP2 axis accumulates the potential energy of inflammation in macrophages. These results identify DPEP2 as a key regulator of macrophage-mediated intestinal inflammation. Thus, the Trim32-DPEP2 axis may be a potential therapeutic target for the treatment of intestinal inflammation.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"90 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The SETDB1-PC4-UPF1 post-transcriptional machinery controls periodic degradation of CENPF mRNA and maintains mitotic progression","authors":"Qimei Pan, Peng Luo, Yuntan Qiu, Kaishun Hu, Lehang Lin, Heyun Zhang, Dong Yin, Chunmeng Shi","doi":"10.1038/s41418-025-01465-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01465-z","url":null,"abstract":"<p>Numerous genes exhibit periodic oscillations in mRNA expression, essential for orderly cell division. Mitosis-related mRNAs fluctuate cyclically from the G2 to M phase, primarily regulated by transcription factors. However, the role of post-transcriptional regulation in this process remains unclear. Here, we demonstrated a decrease in mRNA levels of centromere protein F (<i>CENPF</i>) from the early to late G2 phase. SETDB1-PC4-UPF1 serves as a crucial post-transcriptional machinery, orchestrating the periodic degradation of <i>CENPF</i> mRNA, ensuring balanced CENP expression, proper spindle assembly, and successful mitosis. In early G2, newly synthesized <i>CENPF</i> mRNAs accumulate and bind to PC4, leading to SETDB1-mediated PC4 dimethylation at K35. In late G2, dimethylated PC4 interacts with UPF1 to promote deadenylation-dependent degradation of <i>CENPF</i> mRNAs, forming a regulatory loop for CENP homeostasis. Elevated PC4 dimethylation in hepatocellular carcinoma, coupled with increased sensitivity to taxanes upon its inhibition, suggests promising therapeutic avenues. These findings suggest a post-transcriptional quality control mechanism regulating cyclic mitotic mRNA fluctuations, providing comprehensive insights into cell cycle gene regulation dynamics.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop","authors":"Junjun Xiong, Xuhui Ge, Dishui Pan, Yufeng Zhu, Yitong Zhou, Yu Gao, Haofan Wang, Xiaokun Wang, Yao Gu, Wu Ye, Honglin Teng, Xuhui Zhou, Zheng Wang, Wei Liu, Weihua Cai","doi":"10.1038/s41418-025-01467-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01467-x","url":null,"abstract":"<p>Astrocytic metabolic reprogramming is an adaptation of metabolic patterns to meet increased energy demands, although the role after spinal cord injury (SCI) remains unclear. Analysis of single-cell RNA sequencing (scRNA-seq) data identified an increase in astrocytic glycolysis, while PFKFB3, a key regulator of glycolytic flux, was significantly upregulated following SCI. Loss of PFKFB3 in astrocytes prohibited neuronal energy supply and enhanced neuronal ferroptosis in vitro and expanded infiltration of CD68⁺ macrophages/microglia, exacerbated neuronal loss, and hindered functional recovery in vivo after SCI. Mechanistically, deubiquitinase UCHL1 plays a crucial role in stabilizing and enhancing PFKFB3 expression by cleaving K48-linked ubiquitin chains. Genetic deletion of <i>Uchl1</i> inhibited locomotor recovery after SCI by suppression of PFKFB3-induced glycolytic reprogramming in astrocytes. Furthermore, the UCHL1/PFKFB3 axis increased lactate production, leading to enhanced histone lactylation and subsequent transcription of <i>Uchl1</i> and several genes related to glycolysis, suggesting a glycolysis/H4K8la/UCHL1 positive feedback loop. These findings help to clarify the role of the UCHL1/PFKFB3/H4K8la loop in modulation of astrocytic metabolic reprogramming and reveal a potential target for treatment of SCI.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosomal 3p loss and 8q gain drive vasculogenic mimicry via HIF-2α and VE-cadherin activation in uveal melanoma","authors":"Daniel Delgado-Bellido, Antonio Chacon-Barrado, Joaquin Olmedo-Pelayo, Carmen Jordán Perez, Paula Gilabert-Prieto, Juan Díaz-Martin, Angel Garcia-Diaz, F. J. Oliver, Enrique de Álava","doi":"10.1038/s41418-025-01469-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01469-9","url":null,"abstract":"<p>Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and is where Vasculogenic Mimicry (VM) was first described. VM enables aggressive cancer cells to independently form blood networks, complicating treatment for patients exhibiting VM. Previous studies linked VE-Cadherin phosphorylation at Y658 to gene expression via Focal Adhesion Kinase (FAK), enhancing the Kaiso/β-catenin/TCF-4 complex associated with VE-Cadherin and thereby promoting VM. Recently, an allosteric HIF-2α inhibitor (Belzutifan) was FDA-approved for VHL-associated ccRCCs. In this research, we elucidate the primary causes of VM formation in UM patients with chromosome 3p loss and chromosome 8q gain, identifying VHL, BAP1, and FAK as important factors driving VM and worsening prognosis. These factors promote abnormal activation of HIF-2α and VE-Cadherin under basal hypoxic conditions, leading to VM formation. Cytoscan 750k experiments on the MUM 2B cell line reveal a loss of chromosome 3p, where the VHL, BAP1, and CTNNB1 genes are located, and a gain of chromosome 8q (FAK), whereas the MUM 2C cell line shows a gain of chromosome 3p. This provides an outstanding cross-sectional model from patient samples to established cell lines for VM studies. LC-MS experiments demonstrate that VE-Cad/ENG expression is related to FAK activity in UM cell lines. Finally, using a combination of Belzutifan (HIF-2α inhibitor) and FAK inhibitor (FAKi), we observed a significant reduction in UM xenografts. Our results lead us to propose combining Belzutifan and FAKi as a personalized treatment strategy for UM patients. This approach inhibits VM formation and counters the initial hypoxic conditions resulting from chromosome 3p loss and chromosome 8q gain in UM patients, instilling confidence in the potential of this treatment strategy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collaborative orchestration of BH3-only proteins governs Bak/Bax-dependent hepatocyte apoptosis under antiapoptotic protein-deficiency in mice","authors":"Shinnosuke Kudo, Hayato Hikita, Yoshinobu Saito, Kazuhiro Murai, Takahiro Kodama, Tomohide Tatsumi, Tetsuo Takehara","doi":"10.1038/s41418-025-01458-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01458-y","url":null,"abstract":"<p>The fine-tuned balance between anti-apoptotic Bcl-2 family proteins, such as Bcl-xL and Mcl-1, and pro-apoptotic Bcl-2 family proteins, like Bak and Bax, is crucial for maintaining hepatocyte integrity. BH3-only proteins, including Bid, Bim, Puma, Noxa, Bad, Bmf, Bik and Hrk, serve as apoptosis initiators. They are activated by various stimuli, which leads to Bak/Bax activation. We previously reported that Bid and Bim contributed to hepatocyte apoptosis through Bak/Bax activation in the absence of anti-apoptotic proteins Bcl-xL and/or Mcl-1. However, the comprehensive involvement of all eight BH3-only proteins in Bak/Bax-dependent hepatocyte apoptosis remains unclear. Puma disruption suppressed hepatocyte apoptosis in hepatocyte-specific Bcl-xL or Mcl-1 knockout (Bcl-xL^ΔHep/ΔHep or Mcl-1^ΔHep/ΔHep) mice. Disruption of Bid and Bim partially prevented lethality in Mcl-1^ΔHep/+ Bcl-xL^ΔHep/ΔHep mice, although severe hepatocyte apoptosis persisted, which was suppressed by additional Puma disruption. However, hepatocyte apoptosis was still induced compared to that in Mcl-1^ΔHep/+ Bcl-xL^ΔHep/ΔHep Bax^ΔHep/ΔHep Bak^−/− mice. Triple disruption of Bid, Bim and Puma did not prevent induction of hepatocyte apoptosis in tamoxifen-induced Mcl-1^{iΔHep/iΔHep} Bcl-xL^{iΔHep/iΔHep} mice. Primary hepatocytes, isolated from Mcl-1^fl/fl Bcl-xL^fl/fl Bid^−/− Bim^−/− Puma^−/− mice and immortalized, underwent apoptosis with doxycycline-dependent Cre recombination. Among the remaining five BH3-only proteins, Bik and Hrk were not expressed in these cells, and Noxa knockdown, but not Bad or Bmf knockdown, reduced apoptosis. Noxa disruption alleviated hepatocyte apoptosis in Mcl-1^ΔHep/ΔHep mice and tamoxifen-induced Mcl-1^{iΔHep/iΔHep} Bcl-xL^{iΔHep/iΔHep} Bid^−/− Bim^−/− Puma^−/− mice, prolonging survival. Apoptosis persisted in immortalized primary hepatocytes isolated from Mcl-1^fl/fl Bcl-xL^fl/fl Bid^−/− Bim^−/− Puma^−/− Noxa^−/− mice where doxycycline-dependent Cre recombination was induced, but was completely suppressed by Bak/Bax knockdown, while Bad or Bmf knockdown had no effect. In conclusion, among the eight BH3-only proteins, Puma and Noxa, alongside Bid and Bim, contributed to Bak/Bax-dependent hepatocyte apoptosis, but not indispensably, in the absence of Mcl-1 and Bcl-xL.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 5 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tripartite motif-containing protein 26 promotes colorectal cancer growth by inactivating p53","authors":"Zhihui Tan, Hyun Min Ko, Parnian Naji, Rong Zhu, Jieqiong Wang, Shibo Huang, Yiwei Zhang, Shelya X. Zeng, Hua Lu","doi":"10.1038/s41418-025-01463-1","DOIUrl":"https://doi.org/10.1038/s41418-025-01463-1","url":null,"abstract":"<p>Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that exhibits divergent roles in various cancer types (oncogenic and anti-oncogenic). This study investigates the interaction of TRIM26 with the tumor suppressor protein p53 in colorectal cancer (CRC) cells by performing a comprehensive set of biochemical, cell-based assays, and xenograft experiments. As a result, we found that overexpression of TRIM26 significantly enhances CRC cell proliferation and colony formation, while knockdown of TRIM26 suppresses these processes. Xenograft experiments further validated the tumor-promoting role of TRIM26 in CRC. Supporting this is that TRIM26 is highly expressed in human CRC tissues as revealed by our analysis of the TCGA database. Biochemically, TRIM26 directly bound to the C-terminus of p53 and facilitated its ubiquitination, resulting in proteolytic degradation and attenuated p53 activity independently of MDM2. Also, TRIM26 increased the MDM2-mediated ubiquitination of p53 by binding to MDM2’s C-terminus. This study uncovers the oncogenic potential of TRIM26 in CRC by inhibiting p53 function. Through its ubiquitin ligase activity, TRIM26 destabilizes p53, consequently promoting CRC cell proliferation and tumor growth. These findings shed light on the complex involvement of TRIM26 in cancer and identify this ubiquitin ligase as a potential therapeutic target for future development of CRC treatment.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"18 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP38 functions as an oncoprotein by downregulating the p53 pathway through deubiquitination and stabilization of MDM2","authors":"Shanyu Zhao, Xiaoli Liu, Rongkui Luo, Zitao Jian, Chen Xu, Yingyong Hou, Xiuping Liu, Pingzhao Zhang","doi":"10.1038/s41418-025-01462-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01462-2","url":null,"abstract":"<p>Dysregulation of the MDM2-p53 pathway is a commonly observed phenomenon in cancer, where overexpression or amplification of MDM2 leads to increased degradation of p53. This results in reduced levels of p53, leading to the loss of its tumor-suppressive functions. The study focused on investigating the role of Ubiquitin-specific protease 38 (USP38) in cancer and its interaction with the MDM2-p53 axis. We revealed that USP38 positively correlates with MDM2 and negatively correlates with p53 expression. Mechanistically, USP38 directly binds to MDM2, functioning as a deubiquitinating enzyme (DUB) to stabilize MDM2 and suppress p53 expression. Knockout of USP38 hindered cancer cell proliferation, migration, and invasion, and enhanced apoptosis. Moreover, USP38 deficiency increased sensitivity to chemotherapy drugs and promoted ferroptosis in gastric and breast cancer cell lines. Importantly, these effects were found to be dependent on p53, as the downregulation of p53 reversed the phenotypic changes induced by USP38 knockout. These findings shed light on the oncogenic role of USP38 by modulating the MDM2-p53 axis, providing valuable insights into the molecular mechanisms of USP38 in cancer and potential therapeutic strategies for gastric and breast cancer.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSTF2-impeded innate αβ T cell infiltration and activation exacerbate immune evasion of pancreatic cancer","authors":"Xiaowei He, Ji Liu, Yifan Zhou, Sihan Zhao, Ziming Chen, Zilan Xu, Chunling Xue, Lingxing Zeng, Shuang Liu, Shaoqiu Liu, Ruihong Bai, Shaojia Wu, Lisha Zhuang, Mei Li, Hongzhe Zhao, Quanbo Zhou, Dongxin Lin, Jian Zheng, Xudong Huang, Jialiang Zhang","doi":"10.1038/s41418-025-01464-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01464-0","url":null,"abstract":"<p>Alternative cleavage and polyadenylation (APA) have gained increasing attention in cancer biology, yet its role in modulating anti-tumor immune response remains largely unexplored. Here, we identify the cleavage stimulation factor 2 (<i>CSTF2</i>), an APA-related gene, as a pivotal suppressor of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDAC). <i>CSTF2</i> promotes tumor development by inhibiting the infiltration and cytotoxic immune cell recruitment function of TCRαβ⁺CD4⁻CD8⁻NK1.1⁻ innate αβ T (iαβT) cells. Mechanistically, CSTF2 diminishes CXCL10 expression by promoting PolyA polymerase alpha (PAPα) binding to the 3’ untranslated regions of <i>CXCL10</i> RNA, resulting in shortened PolyA tails and compromised RNA stability. Furthermore, we identify Forsythoside B, a selective inhibitor targeting the RNA recognition motif of CSTF2, can effectively activate anti-tumor immunity and overcome resistance to immune checkpoint blockade (ICB) therapy. Collectively, our findings unveil CSTF2 as a promising therapeutic target for sensitizing PDAC to ICB therapy.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}