Cell Death & Disease最新文献

{"title":"KLF13 promotes esophageal cancer progression and regulates triacylglyceride and free fatty acid metabolism through GPIHBP1.","authors":"Pengjie Yang, Benben Zhu, Hongwei Cui, Yongjun Yu, Qin Yu, Linghui Kong, Mengfei Sun, Yuan Liu, Bateer Han, Shuchen Chen","doi":"10.1038/s41419-025-07709-7","DOIUrl":"10.1038/s41419-025-07709-7","url":null,"abstract":"<p><p>Kruppel-Like Factor 13 (KLF13) has strong effects on cancer occurrence and progression. Nevertheless, the role of KLF13 in oesophagal cancer (EC) remain elusive. In this study, we detected the expression of KLF13 in EC tissues and cells using immunohistochemistry, western blot, and real-time PCR, and found that KLF13 was upregulated in EC tissues and cells compared to normal controls. High expression of KLF13 indicated a poor prognosis for EC patients. Further, function studies in vitro and in vivo were performed to explore the role of KLF13 in EC cell progression. The results revealed that KLF13 knockdown suppressed EC cell proliferation, migration, epithelial-mesenchymal transition, increased cell apoptosis and cell cycle arrest in vivo and inhibited tumour growth in vitro. Conversely, KLF13 overexpression in EC cells had the opposite consequences. Mechanically, differentially expressed genes downstream of KLF13 were identified by RNA-seq and ChIP-seq. We found that there is a positive correlation between triacylglyceride and free fatty acid levels and KLF13 expression levels. A lipid-related gene, Glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1), was identified as a downstream gene of KLF13 using luciferase and chromatin immunoprecipitation assays, whose expression was positively regulated by KLF13. Finally, in vitro and in vivo recovery assays using shRNAs and overexpression plasmids confirmed that KLF13 has an oncogenic role in EC progression through GPIHBP1. Collectively, KLF13 can promote EC progression, triacylglyceride and free fatty acid metabolism through GPIHBP1. Therefore, molecular therapies targeting KLF13 and GPIHBP1 may be effective treatments against EC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"425"},"PeriodicalIF":8.1,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191563","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":"FGFR4 promotes CAF activation through the CXCL10-CXCR3 axis in colon cancer.","authors":"Eun-Gene Sun, Ji-Na Choi, Mi-Ra Park, Dae-Hwan Kim, MinJeong Sung, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Chaeyong Jung, Young-Kook Kim, Ik-Joo Chung, Sang-Hee Cho","doi":"10.1038/s41419-025-07588-y","DOIUrl":"10.1038/s41419-025-07588-y","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) promote the malignant phenotype of cancer through crosstalk with tumor and immune cells within the tumor microenvironment. Therefore, the mechanisms underlying CAF activation require in-depth study to develop strategies targeting CAFs during cancer immunotherapy. In this study, we investigated the role of FGFR4 in CAF regulation in colon cancer. FGFR4-overexpressing cancer cells promoted CAF abundance and activation in vivo, while also inducing the differentiation of normal fibroblasts into CAFs via their secretome. Mechanistically, FGFR4 induced CXC-chemokine ligand (CXCL) 10 production by upregulating Toll-like receptor 3-interferon regulatory factor-interferon beta (IFNβ) signaling and the autocrine action of IFNβ. CXCL10 increased CAF marker expression in fibroblasts, including alpha-smooth muscle actin and vimentin. CXCL10 also promoted CAF migration, invasion, and contractibility, which reflects CAF activation. In contrast, knocking down CXCL10 or neutralizing antibodies abolished CAF marker expression in fibroblasts. Inhibition of CXC receptor type (CXCR) 3, the cognate receptor of CXCL10, also impaired CAF function. In human colon cancer samples, FGFR4 and CXCL10 expression was positively correlated with CAF marker expression. Finally, dual inhibition of FGFR4 and CXCR3 suppressed tumor growth, accompanied by CAF downregulation. Our findings reveal the mechanism through which FGFR4 promotes CAF differentiation/activation in TME via the CXCL10-CXCR3 axis, highlighting the potential of co-targeting FGFR4 and CXCR3 as a therapeutic strategy for patients with stromal-dominant tumors.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"424"},"PeriodicalIF":8.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186655","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":"Reln-Dab1 pathway mitigates retinal ganglion cell apoptosis in retinal ischemia-reperfusion injury.","authors":"Ning Xu, Zongyuan Li, Xiangwen Zeng, Yilin Jiang, Tunan Sun, Shuyu Liu, Na Li, Zhao Li, Yifei Huang, Liqiang Wang","doi":"10.1038/s41419-025-07742-6","DOIUrl":"10.1038/s41419-025-07742-6","url":null,"abstract":"<p><p>Ischemia-reperfusion (I/R) injury is associated with a variety of retinal diseases, resulting in loss of the number of ganglion cells (RGCs), retinal structural disorders, and retinal dysfunction. The Reelin protein is an important regulator of neuronal migration and synaptogenesis, and the Reln signaling pathway plays an essential role in regulating the targeted projection of RGC dendrites and neuronal survival, which has not been reported in retinal I/R injury. The aim of this study was to investigate the expression, role and mechanism of Reln in retinal I/R injury. By establishing Reln-CreERT2 mTmG transgenic mice, it was observed that the expression of Reln initially decreased and then increased after retinal I/R injury. After supplementing exogenous Reelin protein and adeno-associated virus (AAV)-targeted regulation of Reln in vivo, morphological and functional experiments demonstrated its effectiveness in protecting RGCs survival, maintaining morphological integrity of the retina, and inhibiting post-injury retinal dysfunction. Furthermore, integrin β1 (Itgb1) was identified as the main receptor through which Reelin exerts neuroprotective effects while regulating retinal I/R injury repair through the Dab1-PI3K-Akt pathway. These findings provide evidence supporting Reln pathway's role in maintaining retinal homeostasis and facilitating injury repair. Moreover, these findings have significant implications for identifying new targets for preventing and treating various retinal diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"423"},"PeriodicalIF":8.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180750","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":"N-glycosylated LTβR increases the Th17/Treg cell ratio in liver cancer by blocking RORC ubiquitination and FOXP3 transcription.","authors":"Banglun Pan, Yuxin Yao, Hao Wu, Dongjie Ye, Zhu Zhang, Xinyu Zhang, Xiaoqian Wang, Nanhong Tang","doi":"10.1038/s41419-025-07738-2","DOIUrl":"10.1038/s41419-025-07738-2","url":null,"abstract":"<p><p>LTβR-overexpressing CAR-T cells have demonstrated surprising effectiveness against solid tumors, exhibiting strong anti-exhaustion and proliferation capabilities. However, the role of LTβR in CD4⁺ T cell differentiation and anti-tumor activity remains unclear. In this study, we employed primary or subcutaneous mouse hepatocellular carcinoma (HCC) models and flow cytometry to study the impact of conditional knock-in of Ltbr on CD4⁺ T cell differentiation and response, particularly the Th17/Treg cell ratio, and its influence on HCC progression. Immunoprecipitation, immunoblotting, RT-qPCR, molecular docking, and Chromatin Immunoprecipitation-qPCR were performed to investigate the molecular mechanism of CD4⁺ T cell differentiation. Adeno-associated virus-modified T cells were introduced into patient-derived orthotopic xenograft (PDOX) model to assess the combined impact of LTβR and glycolysis inhibitors on the Th17/Treg cell differentiation. We found that LTβR reduced PELI1 expression, preventing TRAF3 protein degradation in Th17 cells. TRAF3 then competed with RORC for SMURF1 binding, enhancing RORC stability and Th17 cell differentiation. LTβR also blocked PRDM1 expression, delaying Foxp3 transcription and Treg cell infiltration. Additionally, N-glycosylation supported the stability of LTβR by protecting it from ubiquitination. From a therapeutic perspective, glycolysis inhibitors helped LTβR balance the proportion of Th17/Treg cells in PDOX model to inhibit tumor growth. In conclusion, our findings indicated that LTβR N-glycosylation prevented RORC ubiquitination and Foxp3 transcription, raising the Th17/Treg cell ratio and hindering HCC progression.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"421"},"PeriodicalIF":8.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172804","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":"miR-181a-5p mediates the effects of BMP4 on intestinal cell proliferation and differentiation.","authors":"Chang Li, Yuning Zhou, Zhijie Yin, Yinping Jiang, Jinpeng Liu, Heidi L Weiss, Qingding Wang, B Mark Evers","doi":"10.1038/s41419-025-07730-w","DOIUrl":"10.1038/s41419-025-07730-w","url":null,"abstract":"<p><p>The intestinal mucosa undergoes a dynamic process of continual proliferation, differentiation, and apoptosis. Delineating the mechanisms involved in intestinal epithelial cell (IEC) differentiation is crucial to our understanding of not only normal gut adaptation but also aberrant intestinal growth. Bone morphogenetic protein (BMP) signaling is a pivotal regulator of intestinal proliferation and differentiation. However, the molecular underpinnings of the BMP pathway in this context are not entirely known. Here, we show a key role for the BMP4/microRNA (miR)-181/glycolysis signaling pathway in the maintenance of intestinal epithelial cell proliferation and differentiation. Treatment with BMP4 increased the expression of enterocyte markers and decreased proliferation of IECs, and importantly, decreased the expression of miR-181a-5p in mouse and human intestinal organoids. miR-181a-5p is a member of the miR-181 family with the highest expression in IECs. Treatment with locked nucleic acid (LNA) miR-181a-5p inhibitor significantly increased enterocyte differentiation as noted by increased expression of enterocyte markers in human and mouse intestinal organoids. In addition, LNA miR-181a-5p inhibitor repressed intestinal stem cell self-renewal as noted by the decreased organoid forming efficiency and expression of Ki67, cyclin D1, OLFM4 in human and mouse intestinal organoids. Moreover, in vivo administration of LNA miR-181a-5p inhibitor enhanced increased intestinal enterocyte differentiation and repressed intestinal cell proliferation. In contrast, overexpression of miR-181a-5p mimic decreased basal and BMP4-induced expression of enterocyte markers. Moreover, BMP4 treatment or inhibition of miR-181a-5p repressed hexokinase (HK) 1 expression and inhibited glycolysis. Consistently, knockdown of HK1 or inhibition of glycolysis using 2-deoxyglucose (2-DG) promoted enterocyte maturation and inhibited proliferation of IECs. Together, we provide evidence showing that miR-181a-5p inhibits intestinal enterocyte differentiation and promotes IEC proliferation through HK1-dependent glycolysis. Importantly, our findings identify miR-181a-5p as downstream in mediating BMP4 induction of enterocyte differentiation and inhibition of proliferation in IECs.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"420"},"PeriodicalIF":8.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172803","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":"VCPIP1 facilitates pancreatic adenocarcinoma progression via Hippo/YAP signaling.","authors":"Zhihao Liu, Chenmiao Zhang, Yingwen Gai, Peng Su, Beibei Wang, Peng Liu, Limin Wang, Yue Lin, Jian Zhu, Xiaodong Tan","doi":"10.1038/s41419-025-07746-2","DOIUrl":"10.1038/s41419-025-07746-2","url":null,"abstract":"<p><p>Dysregulation of Hippo signaling is observed in pancreatic adenocarcinoma (PAAD). Moreover, overactivation of YAP is crucial for tumor progression. Although the inhibitory phospho-cascade is functional, the reason for YAP hyperactivation in PAAD remains unclear. Recent studies have revealed that the ubiquitin modification of YAP also plays an important role in the Hippo/YAP axis and cancer progression. To gain a better understanding of the potential mechanisms underlying the ubiquitination and deubiquitination of YAP, we carried out siRNA screening for critical deubiquitinases in PAAD. By using a deubiquitinase (DUB) library, we identified valosin-containing protein-interacting protein 1 (VCPIP1) as an important effector of YAP function and PAAD progression. Inhibition of VCPIP1 hampered PAAD progression via Hippo signaling. Clinical data revealed that VCPIP1 was elevated in PAAD and correlated with poor survival in PAAD patients. Biochemical assays demonstrated that VCPIP1 interacted with YAP, inhibiting K48-linked polyubiquitination and thereby increasing YAP stability. YAP directly binds to the VCPIP1 promoter region, enhancing its transcription in PAAD. Our study revealed a forward feedback loop between VCPIP1 and Hippo signaling in PAAD, indicating that VCPIP1 is a potential therapeutic drug target in PAAD.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"422"},"PeriodicalIF":8.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172805","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":"MMA-induced LOXL2⁺ PSCs promote linear ECM alignment in the aging pancreas leading to pancreatic cancer progression.","authors":"Wenyuan Shi, Haodong Tang, Siyuan Tan, Lishan Wang, Zeqian Yu, Shan Gao, Jiahua Zhou","doi":"10.1038/s41419-025-07751-5","DOIUrl":"10.1038/s41419-025-07751-5","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is an age-associated malignancy closely linked to the extracellular matrix (ECM). However, the impact of age-related ECM changes in the normal pancreas on PDAC progression remains unclear. Here, we find that increased linear ECM alignment in normal pancreatic tissues from aged PDAC patients is associated with PDAC progression and worse outcomes. Furthermore, serum methylmalonic acid (MMA) levels are elevated in aged PDAC patients and associated with increased linear ECM alignment in normal pancreatic tissues of PDAC patients. Functionally, MMA promotes LOXL2 expression in pancreatic stellate cells (PSCs), increases linear ECM alignment in normal pancreatic tissues, and facilitates tumor progression. Mechanistically, MMA upregulates KLF10, which forms a transcriptional complex with SP1 to enhance LOXL2 expression in PSCs. Our study demonstrates the role of MMA-induced LOXL2⁺PSCs in ECM remodeling, thus serving as a potential therapeutic target to mitigate PDAC progression in aged patients. Schematic diagram showing the molecular mechanism by which MMA-induced LOXL⁺PSCs promote PDAC progression in the aging pancreas. In aged individuals, elevated levels of MMA in the blood induce the activation of the KLF10/SP1‒LOXL2 axis in PSCs to increase linear ECM alignment. Following the initiation of pancreatic cancer, this increased linear ECM alignment leads to increased tumor invasion into surrounding tissues, resulting in a greater proportion of stage T3/T4 tumors and a greater incidence of LVI and PNI in aged patients, ultimately leading to poorer outcomes (This schematic was created with www.figdraw.com ,export id: PRPRS4e268).</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"419"},"PeriodicalIF":8.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156688","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: Absence of cyclin-dependent kinase inhibitor p27 or p18 increases efficiency of iPSC generation without induction of iPSC genomic instability.","authors":"Zhiyan Zhan, Lili Song, Weiwei Zhang, Haihui Gu, Haizi Cheng, Yingwen Zhang, Yi Yang, Guangzhen Ji, Haizhong Feng, Tao Cheng, Yanxin Li","doi":"10.1038/s41419-025-07728-4","DOIUrl":"10.1038/s41419-025-07728-4","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"417"},"PeriodicalIF":8.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149428","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":"The TP53 Arg72Pro polymorphism predicts visual and neurodegenerative outcomes in retinal detachment.","authors":"Nadia Galindo-Cabello, Eva M Sobas-Abad, Rebeca Lapresa, Jesús Agulla, Ángeles Almeida, Antonio López, José Carlos Pastor, Salvador Pastor-Idoate, Ricardo Usategui-Martín","doi":"10.1038/s41419-025-07739-1","DOIUrl":"10.1038/s41419-025-07739-1","url":null,"abstract":"<p><p>Retinal detachment (RD) separates the retina from the retinal epithelium, causing photoreceptor apoptosis and irreversible vision loss. Even with successful surgical reattachment, complete visual recovery is not guaranteed. The TP53 Arg72Pro polymorphism, implicated in apoptosis, has emerged as a potential predictor of RD outcomes. We investigated the impact of the Arg72Pro polymorphism on retinal neurodegeneration and functional recovery in patients. The underlying mechanisms were analyzed in a humanized TP53 Arg72Pro RD mouse model. In a cohort of 180 patients, carriers of the Pro allele exhibited decreased apoptotic gene expression and improved visual recovery. Complementary findings in mice revealed that the Pro variant preserved photoreceptor integrity and reduced apoptosis rates following RD. Our findings highlight the potential of this TP53 polymorphism as a biomarker for RD outcomes and a tool for tailoring therapies. This study underscores the importance of integrating genetic profiling into personalized medicine approaches to improve recovery of RD patients' visual outcomes.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"415"},"PeriodicalIF":8.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149433","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: METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA.","authors":"Liping Meng, Hui Lin, Xingxiao Huang, Jingfan Weng, Fang Peng, Shengjie Wu","doi":"10.1038/s41419-025-07680-3","DOIUrl":"10.1038/s41419-025-07680-3","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"416"},"PeriodicalIF":8.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149430","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}