Cell Death Discovery最新文献

{"title":"N4BP3 facilitates NOD2-MAPK/NF-κB pathway in inflammatory bowel disease through mediating K63-linked RIPK2 ubiquitination.","authors":"Wang Jiang, Yan Zhao, Min Han, Jiafan Xu, Kun Chen, Yi Liang, Jie Yin, Jinyue Hu, Yueming Shen","doi":"10.1038/s41420-024-02213-x","DOIUrl":"https://doi.org/10.1038/s41420-024-02213-x","url":null,"abstract":"<p><p>The NOD2 signaling pathway, which plays an important role in the mechanisms of inflammatory bowel disease (IBD) development, has been closely associated with ubiquitination. It was revealed in this study that NOD2 receptor activation could obviously affect the expression of 19 ubiquitination-related genes, with N4BP3 being the most prominently expressed and upregulated. In addition, N4BP3 knockdown was found to reduce the mRNA levels of MDP-induced inflammatory factors, while N4BP3 overexpression elevated their mRNA levels as well as the levels of phospho-ERK1/2, phospho-JNK, phospho-P38 and phospho-NF-κB P65 proteins. Immunoprecipitation tests showed that N4BP3 could pull down RIPK2 and promote its K63-linked ubiquitination. In human tissue specimen assays and mouse experiments, we found that the expression of N4BP3 was significantly elevated in Crohn's disease (CD) patients and IBD mice, and N4BP3 knockdown reduced the dextran sulfate sodium-induced pathological score and the expression of inflammatory factors in the mouse colon tissue. In conclusion, N4BP3 is able to interact with RIPK2 and promote its K63-linked ubiquitination, to further promote the NOD2-MAPK/NF-κB pathway, thereby increasing promoting the release of inflammation factors and the degree of IBD inflammation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"440"},"PeriodicalIF":6.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459034","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":"TMEM209 promotes hepatocellular carcinoma progression by activating the Wnt/β-catenin signaling pathway through KPNB1 stabilization.","authors":"Haoran Fang, Xiaoyi Shi, Jie Gao, Zhiping Yan, Yun Wang, Yabin Chen, Jiacheng Zhang, Wenzhi Guo","doi":"10.1038/s41420-024-02207-9","DOIUrl":"https://doi.org/10.1038/s41420-024-02207-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most common malignancy in the liver, with a poor prognosis. Transmembrane protein 209 (TMEM209) involves multiple biological processes, such as substance transportation and signal transduction, and is abundantly expressed in tumor tissues. However, the relationship between TMEM209 and HCC has not been comprehensively elucidated. In this study, we aimed to illustrate this issue by in vitro and in vivo experiments. Bioinformatic analysis and clinical sample validation revealed that TMEM209 was upregulated in HCC and correlated with reduced survival duration. Functionally, TMEM209 promoted the proliferation, migration, invasion, and EMT of HCC cells in vitro and facilitated tumor growth and metastasis in xenograft models. Mechanistically, TMEM209 promoted the proliferation and metastasis of HCC in a KPNB1-dependent manner. Specifically, TMEM209 could bind to KPNB1, thereby competitively blocking the interaction between KPNB1 and the E3 ubiquitin ligase RING finger and CHY zinc finger domain-containing protein 1 (RCHY1) and preventing K48-associated ubiquitination degradation of KPNB1. Ultimately, the Wnt/β-catenin signaling pathway was activated, contributing to the progression of the malignant phenotype of HCC. In conclusion, the molecular mechanism underlying the TMEM209/KPNB1/Wnt/β-catenin axis in HCC progression was elucidated. TMEM209 is a potential biomarker and therapeutic target for HCC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"438"},"PeriodicalIF":6.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459038","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":"YTHDC1-mediated microRNA maturation is essential for hematopoietic stem cells maintenance.","authors":"Hongna Zuo, Jin Liu, Bin Shen, Yue Sheng, Zhenyu Ju, Hu Wang","doi":"10.1038/s41420-024-02203-z","DOIUrl":"https://doi.org/10.1038/s41420-024-02203-z","url":null,"abstract":"<p><p>YTHDC1, a reader of N6-methyladenosine (m⁶A) modifications on RNA, is posited to exert significant influence over RNA metabolism. Despite its recognized importance, the precise function and underlying mechanisms of YTHDC1 in the preservation of normal hematopoietic stem cell (HSCs) homeostasis remain elusive. Here, we investigated the role of YTHDC1 in normal hematopoiesis and HSCs maintenance in vivo. Utilizing conditional Ythdc1 knockout mice and Ythdc1/Mettl3 double knockout mice, we demonstrated that YTHDC1 is required for HSCs maintenance and self-renewal by regulating microRNA maturation. YTHDC1 deficiency resulted in HSCs apoptosis. Furthermore, we uncovered that YTHDC1 interacts with HP1BP3, a nuclear RNA binding protein involved in microRNA maturation. Deletion of YTHDC1 brought about significant alterations in microRNA levels. However, over-expression of mir-125b, mir-99b, and let-7e partially rescued the functional defect of YTHDC1-null HSCs. Taken together, these findings indicated that the nuclear protein YTHDC1-HP1BP3-microRNA maturation axis is essential for the long-term maintenance of HSCs.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"439"},"PeriodicalIF":6.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459040","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":"Author Correction: Establishing safe high hydrostatic pressure devitalization thresholds for autologous head and neck cancer vaccination and reconstruction.","authors":"Claudia Maletzki, Vivica Freiin Grote, Friederike Kalle, Thoralf Kleitke, Annette Zimpfer, Anne-Sophie Becker, Wendy Bergmann-Ewert, Anika Jonitz-Heincke, Rainer Bader, Brigitte Vollmar, Stephan Hackenberg, Agmal Scherzad, Robert Mlynski, Daniel Strüder","doi":"10.1038/s41420-024-02172-3","DOIUrl":"https://doi.org/10.1038/s41420-024-02172-3","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"437"},"PeriodicalIF":6.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458994","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":"Polyploidy mitigates the impact of DNA damage while simultaneously bearing its burden.","authors":"Kazuki Hayashi, Kisara Horisaka, Yoshiyuki Harada, Yuta Ogawa, Takako Yamashita, Taku Kitano, Masahiro Wakita, Takahito Fukusumi, Hidenori Inohara, Eiji Hara, Tomonori Matsumoto","doi":"10.1038/s41420-024-02206-w","DOIUrl":"https://doi.org/10.1038/s41420-024-02206-w","url":null,"abstract":"<p><p>Polyploidy is frequently enhanced under pathological conditions, such as tissue injury and cancer in humans. Polyploidization is critically involved in cancer evolution, including cancer initiation and the acquisition of drug resistance. However, the effect of polyploidy on cell fate remains unclear. In this study, we explored the effects of polyploidization on cellular responses to DNA damage and cell cycle progression. Through various comparisons based on ploidy stratifications of cultured cells, we found that polyploidization and the accumulation of genomic DNA damage mutually induce each other, resulting in polyploid cells consistently containing more genomic DNA damage than diploid cells under both physiological and stress conditions. Notably, despite substantial DNA damage, polyploid cells demonstrated a higher tolerance to its impact, exhibiting delayed cell cycle arrest and reduced secretion of inflammatory cytokines associated with DNA damage-induced senescence. Consistently, in mice with ploidy tracing, hepatocytes with high ploidy appeared to potentially persist in the damaged liver, while being susceptible to DNA damage. Polyploidy acts as a reservoir of genomic damage by mitigating the impact of DNA damage, while simultaneously enhancing its accumulation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"436"},"PeriodicalIF":6.1,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459035","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":"Amodiaquine ameliorates stress-induced premature cellular senescence via promoting SIRT1-mediated HR repair.","authors":"Jie Du, Fuqiang Chen, Chenghong Du, Wenna Zhao, Zihan Chen, Zhenhua Ding, Meijuan Zhou","doi":"10.1038/s41420-024-02201-1","DOIUrl":"10.1038/s41420-024-02201-1","url":null,"abstract":"<p><p>DNA damage is considered to be a potentially unifying driver of ageing, and the stalling of DNA damage repair accelerates the cellular senescence. However, augmenting DNA repair has remained a great challenge due to the intricate repair mechanisms specific for multiple types of lesions. Herein, we miniaturized our modified detecting system for homologous recombination (HR) into a 96-well-based platform and performed a high-throughput chemical screen for FDA-approved drugs. We uncovered that amodiaquine could significantly augment HR repair at the noncytotoxic concentration. Further experiments demonstrated that amodiaquine remarkably suppressed stress-induced premature cellular senescence (SIPS), as evidenced by senescence-associated beta-galactosidase (SA-β-gal) staining or senescence-related markers p21^WAF1 and p16^ink4a, and the expression of several cytokines. Mechanistic studies revealed that the stimulation of HR repair by amodiaquine might be mostly attributable to the promotion of SIRT1 at the transcriptional level. Additionally, SIRT1 depletion abolished the amodiaquine-mediated effects on DNA repair and cellular senescence, indicating that amodiaquine delayed the onset of SIPS via a SIRT1-dependent pathway. Taken together, this experimental approach paved the way for the identification of compounds that augment HR activity, which could help to underscore the therapeutic potential of targeting DNA repair for treating aging-related diseases.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"434"},"PeriodicalIF":6.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406171","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":"Glycolysis-mTORC1 crosstalk drives proliferation of patient-derived endometrial cancer spheroid cells with ALDH activity.","authors":"Haruka Ueda, Tatsuya Ishiguro, Yutaro Mori, Kaoru Yamawaki, Koji Okamoto, Takayuki Enomoto, Kosuke Yoshihara","doi":"10.1038/s41420-024-02204-y","DOIUrl":"10.1038/s41420-024-02204-y","url":null,"abstract":"<p><p>Cancer stem cells are associated with aggressive phenotypes of malignant tumors. A prominent feature of uterine endometrial cancer is the activation of the PI3K-Akt-mTOR pathway. In this study, we present variations in sensitivities to a PI3K-Akt-mTORC1 inhibitor among in vitro endometrial cancer stem cell-enriched spheroid cells from clinical specimens. The in vitro sensitivity was consistent with the effects observed in in vivo spheroid-derived xenograft tumor models. Our findings revealed a complementary suppressive effect on endometrial cancer spheroid cell growth with the combined use of aldehyde dehydrogenase (ALDH) and PI3K-Akt inhibitors. In the PI3K-Akt-mTORC1 signaling cascade, the influence of ALDH on mTORC1 was partially channeled through retinoic acid-induced lactate dehydrogenase A (LDHA) activation. LDHA inhibition was found to reduce endometrial cancer cell growth, aligning with the effects of mTORC1 inhibition. Building upon our previous findings highlighting ALDH-driven glycolysis through GLUT1 in uterine endometrial cancer spheroid cells, curbing mTORC1 enhanced glucose transport via GLUT1 activation. Notably, elevated LDHA expression correlated with adverse clinical survival and escalated tumor grade, especially in advanced stages. Collectively, our findings emphasize the pivotal role of ALDH-LDHA-mTORC1 cascade in the proliferation of endometrial cancer. Targeting the interaction between mTORC1 and ALDH-influenced glycolysis holds promise for developing novel strategies to combat this aggressive cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"435"},"PeriodicalIF":6.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406172","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":"Effective protective mechanisms of HO-1 in diabetic complications: a narrative review.","authors":"Jing-Jing Zhang, Ping Ni, Yi Song, Man-Jun Gao, Xi-Ying Guo, Bao-Qing Zhao","doi":"10.1038/s41420-024-02205-x","DOIUrl":"10.1038/s41420-024-02205-x","url":null,"abstract":"<p><p>Diabetes mellitus is a metabolic disorder with persistent hyperglycemia caused by a variety of underlying factors. Chronic hyperglycemia can lead to diverse serious consequences and diversified complications, which pose a serious threat to patients. Among the major complications are cardiovascular disease, kidney disease, diabetic foot ulcers, diabetic retinopathy, and neurological disorders. Heme oxygenase 1 (HO-1) is a protective enzyme with antioxidant, anti-inflammatory and anti-apoptotic effects, which has been intensively studied and plays an important role in diabetic complications. By inducing the expression and activity of HO-1, it can enhance the antioxidant, anti-inflammatory, and anti-apoptotic capacity of tissues, and thus reduce the degree of damage in diabetic complications. The present study aims to review the relationship between HO-1 and the pathogenesis of diabetes and its complications. HO-1 is involved in the regulation of macrophage polarization and promotes the M1 state (pro-inflammatory) towards to the M2 state (anti-inflammatory). Induction of HO-1 expression in dendritic cells inhibits them maturation and secretion of pro-inflammatory cytokines and promotes regulatory T cell (T_reg cell) responses. The induction of HO-1 can reduce the production of reactive oxygen species, thereby reducing oxidative stress and inflammation. Besides, HO-1 also has an important effect in novel programmed cell death such as pyroptosis and ferroptosis, thereby playing a protective role against diabetes. In conclusion, HO-1 plays a significant role in the occurrence and development of diabetic complications and is closely associated with a variety of complications. HO-1 is anticipated to serve as a novel target for addressing diabetic complications, and it holds promise as a potential therapeutic agent for diabetes and its associated complications. We hope to provide inspiration and ideas for future studies in the mechanism and targets of HO-1 through this review.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"433"},"PeriodicalIF":6.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399456","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":"Mechanisms of ferroptosis and targeted therapeutic approaches in urological malignancies.","authors":"Wenjie Ma, Xiaotian Jiang, Ruipeng Jia, Yang Li","doi":"10.1038/s41420-024-02195-w","DOIUrl":"10.1038/s41420-024-02195-w","url":null,"abstract":"<p><p>The prevalence of urological malignancies remains a significant global health concern, particularly given the challenging prognosis for patients in advanced disease stages. Consequently, there is a pressing need to explore the molecular mechanisms that regulate the development of urological malignancies to discover novel breakthroughs in diagnosis and treatment. Ferroptosis, characterized by iron-ion-dependent lipid peroxidation, is a form of programmed cell death (PCD) distinct from apoptosis, autophagy, and necrosis. Notably, lipid, iron, and glutathione metabolism intricately regulate intracellular ferroptosis, playing essential roles in the progression of various neoplasms and drug resistance. In recent years, ferroptosis has been found to be closely related to urological malignancies. This paper provides an overview of the involvement of ferroptosis in the pathogenesis and progression of urological malignancies, elucidates the molecular mechanisms governing its regulation, and synthesizes recent breakthroughs in diagnosing and treating these malignancies. We aim to provide a new direction for the clinical treatment of urological malignancies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"432"},"PeriodicalIF":6.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388374","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":"CircMETTL3-156aa reshapes the glycolytic metabolism of macrophages to promote M1 polarization and induce cytokine storms in sHLH.","authors":"Longlong Xie, Xiangying Deng, Xiao Li, Xun Li, Xiangyu Wang, Haipeng Yan, Lin Zhao, Dan Yang, Ting Luo, Yufan Yang, Zhenghui Xiao, Xiulan Lu","doi":"10.1038/s41420-024-02202-0","DOIUrl":"10.1038/s41420-024-02202-0","url":null,"abstract":"<p><p>Persistent macrophage activation and cytokine storms are critical causes for the rapid disease progression and high mortality rate of Secondary Hemophagocytic lymphohistiocytosis (sHLH). Identification of key regulatory factors that govern the activation of macrophages is vital. Plasma exosomal circular RNAs (circRNAs) are considered important biomarkers and potential therapeutic targets for various diseases, however, their function in sHLH is still unclear. In this study, we demonstrated for the first time that circMETTL3, derived from METTL3, is upregulated in sHLH patient plasma exosomes, which may plays an important role in the diagnosis of sHLH. Significantly, we also revealed that a novel peptide encoded by circMETTL3, METTL3-156aa, is an inducer of M1 macrophage polarization, which is responsible for the development of cytokine storms during sHLH. We then identified that METTL3-156aa binding with lactate dehydrogenase A (LDHA) and promotes M1 macrophage polarization by enhancing macrophage glycolysis. Additionally, the glycolysis metabolite lactate upregulates the cleavage factor SRSF10 expression by lactylation. This results in increased splicing of the pre-METTL3 mRNA, leading to an enchance in the production of cirMETTL3. Therefore, our results suggest that the circMETTL3/METTL3-156aa/LDHA/Lactate/SRSF10 axis forms a positive feedback loop and may be a novel therapeutic target for the treatment of sHLH.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"431"},"PeriodicalIF":6.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388373","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}