Cell Death & Disease最新文献

{"title":"Oncometabolite fumarate facilitates PD-L1 expression and immune evasion in clear cell renal cell carcinoma.","authors":"Yi Gao, Shiyin Fan, Xue Sun, Jiaxi Li, Yue Dai, Hongchen Li, Haijie Ma, Yanping Xu, Lei Lv","doi":"10.1038/s41419-025-07752-4","DOIUrl":"10.1038/s41419-025-07752-4","url":null,"abstract":"<p><p>Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), with a rising incidence worldwide. However, the mechanisms by which ccRCC evades immune surveillance remain incompletely understood. Our findings indicate that fumarate hydratase (FH) expression is significantly downregulated in ccRCC, resulting in fumarate accumulation, which is correlated with a poor prognosis in ccRCC patients. RNA sequencing analysis suggests that dimethyl fumarate (DMF), an FDA-approved fumarate analogue, may impact tumor immunity. Our further investigation reveals that both DMF and the FH inhibitor (FHIN1) can promote immune evasion in ccRCC by upregulating PD-L1. Pre-treatment of tumor cells with DMF notably inhibits the cytotoxic effect of T cells. Mechanistically, fumarate induces PD-L1 expression through succination of HIF-1α at C800, facilitating its interaction with importin α3, p300, and PKM2, which promotes HIF-1α nuclear localization and transcriptional activity. Moreover, combining DMF with PD-L1 blockade therapy significantly enhances the efficacy of immunotherapy and prolongs the survival of tumor-bearing mice. Taken together, our study elucidates a mechanism by which FH downregulation promotes immune evasion through the fumarate-HIF-1α/p300/PKM2-PD-L1 axis, providing a novel target, drug, and strategy to improve immunotherapy for ccRCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"432"},"PeriodicalIF":8.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215037","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: Mcm5 mutation leads to silencing of Stat1-bcl2 which accelerating apoptosis of immature T lymphocytes with DNA damage.","authors":"Min Liu, Yuanyuan Li, Zhilin Deng, Ke Zhang, Shuying Huang, Jiamin Xia, Yi Feng, Yundan Liang, Chengfu Sun, Xindong Liu, Shurong Li, Bingyin Su, Yong Dong, Sizhou Huang","doi":"10.1038/s41419-025-07674-1","DOIUrl":"10.1038/s41419-025-07674-1","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"429"},"PeriodicalIF":8.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215034","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: Monounsaturated fatty acids promote cancer radioresistance by inhibiting ferroptosis through ACSL3.","authors":"Yulin Cao, Jiuming Li, Ying Chen, Yuanben Wang, Zhiang Liu, Liuying Huang, Bingxin Liu, Yuyang Feng, Surui Yao, Leyuan Zhou, Yuan Yin, Zhaohui Huang","doi":"10.1038/s41419-025-07726-6","DOIUrl":"10.1038/s41419-025-07726-6","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"430"},"PeriodicalIF":8.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215035","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":"Down-regulation of neuroprotective protein kinase D in Huntington´s disease.","authors":"Álvaro Sebastián-Serrano, Ana Simón-García, María Santos-Galindo, Marina Prudencio Sánchez-Carralero, Alberto H-Alcántara, Cristina Clemente, Julia Pose-Utrilla, Miguel R Campanero, Eva Porlan, José J Lucas, Teresa Iglesias","doi":"10.1038/s41419-025-07688-9","DOIUrl":"10.1038/s41419-025-07688-9","url":null,"abstract":"<p><p>Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by the selective dysfunction and loss of neurons in the striatum and cerebral cortex. Experimental evidence suggests that GABAergic medium-sized spiny neurons (MSNs) in the striatum are particularly vulnerable to glutamate-induced toxicity (excitotoxicity) and its analogues. However, the molecular mechanisms underlying MSN-specific death in HD remain poorly understood. The serine/threonine protein kinase D1 (PKD1) confers neuroprotection in various neuropathological conditions, including ischemic stroke. While excitotoxicity inactivates PKD1 in cortical glutamatergic neurons without altering its levels, active PKD1 potentiates the survival of excitatory neurons in highly excitotoxic environments. Here, we investigated whether PKD1 activity dysregulation contributes to MSN death in HD and its association with neurodegeneration. We found an unexpected reduction in PKD1 protein levels in striatal neurons from HD patients. Similarly, the R6/1 mouse model of HD exhibited progressive PKD1 protein loss, commencing at early disease stages, accompanied by decreased Prkd1 transcript levels. PKD1 downregulation also occurred in the cerebral cortex of R6/1 mice, but only at late stages. Functionally, pharmacological PKD inhibition in primary striatal neurons exacerbated excitotoxic damage and apoptosis induced by glutamate N-methyl D-aspartate (NMDA) receptors, whereas expression of constitutively active PKD1 (PKD1-Ca) conferred neuroprotection. Furthermore, PKD1-Ca protected against polyQ-induced apoptosis in a cellular model of HD. In a translational approach, intrastriatal lentiviral delivery of PKD1-Ca in symptomatic R6/1 mice prevented the loss of DARPP-32, a molecular marker of MSNs. Collectively, our findings strongly suggest that PKD1 loss-of-function contributes to HD pathogenesis and the selective vulnerability of MSNs. These findings position PKD1 as a promising therapeutic target for mitigating MSN death in HD.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"418"},"PeriodicalIF":8.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215036","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":"FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death.","authors":"Byeong-Ju Kim, Sun Mi Hong, Hyun-Jin Noh, Jihye Kim, Su-Yeon Seon, Jeong-Eun Lee, Da-Hye Jeong, Ju-Mi Park, Sejeong Park, Sanghoon Lee, Jaewoo Kang, Dakeun Lee, Michael J Morgan, You-Sun Kim","doi":"10.1038/s41419-025-07754-2","DOIUrl":"10.1038/s41419-025-07754-2","url":null,"abstract":"<p><p>Receptor-interacting serine/threonine kinase 1 (RIPK1) is a pivotal protein controlling cell death and inflammation. RIPK1 is an attractive therapeutic target, given that the inhibition of RIPK1 kinase activity has been shown to be effective in animal models of human diseases such as autoimmune and neurodegenerative diseases. Here, we screened a collection of drugs with structural similarity to necrostatin-1 (Nec-1), an inhibitor of RIPK1, to assess their abilities to regulate RIPK1-mediated immunogenic cell death. Through this small-scale screening of drugs from ongoing clinical trials and FDA-approved drugs, we discovered that the drug phensuximide could prevent necroptosis by targeting RIPK1 kinase activity. Importantly, phensuximide, which has already been approved by the FDA for the treatment of epilepsy, effectively prevents the kinase activity of RIPK1 without affecting the NF-κB and MAPK pathways. The potency of phensuximide is that it protects against both LPS- and TNF-induced systemic inflammatory response syndrome (SIRS), which are sepsis models involving RIPK1 kinase activity. Our findings suggest that phensuximide may serve as a promising strategy for targeting RIPK1-mediated diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"426"},"PeriodicalIF":8.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207766","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":"Modulation of microglial phagocytosis via the GAS6-MERTK pathway regulates pathological angiogenesis in the mouse oxygen-induced retinopathy model.","authors":"Canelif Yilmaz, Irina Korovina, Anke Witt, Farid Abdallah, Bianca Müller, Carmen Hentsche, Anika Fleischhauer, Stephan Speier, Andreas Deussen, Anne Klotzsche-von Ameln","doi":"10.1038/s41419-025-07744-4","DOIUrl":"10.1038/s41419-025-07744-4","url":null,"abstract":"<p><p>Ischemic retinopathies (IR) are major causes of blindness worldwide. They are characterized by an exuberant hypoxia-driven pathological neovascularization (NV). While it is well accepted that immune cells contribute to both physiological and pathological retinal angiogenesis, our knowledge of various processes and underlying mechanisms, especially in the direct interaction with endothelial cells (EC), is still very limited. Here, we addressed the role of microglial phagocytosis of apoptotic EC in the context of pathological hypoxia-related NV in the mouse oxygen-induced retinopathy model (OIR). We utilized endothelium-specific fluorescent reporter mice to study the kinetics of EC phagocytosis by leukocytes in OIR. Indeed, we observed phagocytic microglia in close proximity to the pathological vessels and an altered phagocytosis rate by flow cytometry compared to controls. We observed a decrease in the phagocytic rate in early hypoxia-driven stages of OIR, whereas in later stages where pathological vessels appear, the phagocytosis rate was increased. Myeloid-specific deletion of the suppressor of cytokine signaling protein 3 (SOCS3) was previously shown to induce increased phagocytic activity due to overexpression of the opsonin molecule growth arrest-specific 6 (GAS6). In myeloid SOCS3-deficient mice, we observed a reduction of pathological NV in OIR. This reduction could be reversed by neutralizing GAS6 via administration of recombinant MERTK protein, the receptor for GAS6 expressed on myeloid cells. Furthermore, exogenous GAS6 supplementation increased microglial phagocytosis in vitro and limited pathological NV in OIR. Our data suggest that the promotion of immune cell phagocytosis by the modulation of the GAS6-MERTK axis might represent a potential target for the treatment of pathological NV in IR.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"428"},"PeriodicalIF":8.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207778","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: Myeloid-derived growth factor alleviates non-alcoholic fatty liver disease alleviates in a manner involving IKKβ/NF-κB signaling.","authors":"Yan Ding, Xiaoli Xu, Biying Meng, Li Wang, Biao Zhu, Bei Guo, Jiajia Zhang, Lin Xiang, Jing Dong, Min Liu, Guangda Xiang","doi":"10.1038/s41419-025-07486-3","DOIUrl":"10.1038/s41419-025-07486-3","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"427"},"PeriodicalIF":8.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207765","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126484/pdf/","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":"OA","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}