Cell Death & Disease最新文献_第2页

RAB4A is a master regulator of cancer cell stemness upstream of NUMB-NOTCH signaling. RAB4A 是 NUMB-NOTCH 信号转导上游的癌细胞干性主调节因子。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-27 DOI: 10.1038/s41419-024-07172-w

Subbulakshmi Karthikeyan, Patrick J Casey, Mei Wang

{"title":"RAB4A is a master regulator of cancer cell stemness upstream of NUMB-NOTCH signaling.","authors":"Subbulakshmi Karthikeyan, Patrick J Casey, Mei Wang","doi":"10.1038/s41419-024-07172-w","DOIUrl":"10.1038/s41419-024-07172-w","url":null,"abstract":"Cancer stem cells (CSCs) are a group of specially programmed tumor cells that possess the characteristics of perpetual cell renewal, increased invasiveness, and often, drug resistance. Hence, eliminating CSCs is a major challenge for cancer treatment. Understanding the cellular programs that maintain CSCs, and identifying the critical regulators for such programs, are major undertakings in both basic and translational cancer research. Recently, we have reported that RAB4A is a major regulator of epithelial-to-mesenchymal transition (EMT) and it does so mainly through regulating the activation of RAC1 GTPase. In the current study, we have delineated a new signaling circuitry through which RAB4A transmits its control of cancer stemness. Using in vitro and in vivo studies, we show that RAB4A, as the upstream regulator, relays signal stepwise to NUMB, NOTCH1, RAC1, and then SOX2 to control the self-renewal property of multiple cancer cells of diverse tissue origins. Knockdown of NUMB, or overexpression of NICD (the active fragment NOTCH1) or SOX2, rescued the in vitro sphere-forming and in vivo tumor-forming abilities that were lost upon RAB4A knockdown. Furthermore, we discovered that the chain of control is mostly through transcriptional regulation at every step of the pathway. The discovery of the novel signaling axis of RAB4A-NUMB-NOTCH-SOX2 opens the path for further expansion of the signaling chain and for the identification of new regulators and interacting proteins important for CSC functions, which can be explored to develop new and effective therapies.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495891","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}

引用次数: 0

Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy. ZBP1 对内源性逆转录病毒衍生 RNA 的感应会触发 DNA 损伤中的泛凋亡，并导致化疗的毒副作用。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-27 DOI: 10.1038/s41419-024-07175-7

Fang Wang, Kaiying Li, Wensheng Wang, Jiang Hui, Jiangping He, Jin Cai, Wenqing Ren, Yaxing Zhao, Qianqian Song, Yuan He, Yanlei Ma, Xiaona Feng, Yue Liu, Jianqiang Yu, Jitkaew Siriporn, Dan Ma, Zhenyu Cai

{"title":"Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy.","authors":"Fang Wang, Kaiying Li, Wensheng Wang, Jiang Hui, Jiangping He, Jin Cai, Wenqing Ren, Yaxing Zhao, Qianqian Song, Yuan He, Yanlei Ma, Xiaona Feng, Yue Liu, Jianqiang Yu, Jitkaew Siriporn, Dan Ma, Zhenyu Cai","doi":"10.1038/s41419-024-07175-7","DOIUrl":"10.1038/s41419-024-07175-7","url":null,"abstract":"Excessive DNA damage triggers various types of programmed cell death (PCD), yet the regulatory mechanism of DNA damage-induced cell death is not fully understood. Here, we report that PANoptosis, a coordinated PCD pathway, including pyroptosis, apoptosis and necroptosis, is activated by DNA damage. The Z-DNA binding protein 1 (ZBP1) is the apical sensor of PANoptosis and essential for PANoptosome assembly in response to DNA damage. We find endogenous retroviruses (ERVs) are activated by DNA damage and act as ligands for ZBP1 to trigger PANoptosis. By using ZBP1 knock-out and knock-in mice disrupting ZBP1 nucleic acid-binding activity, we demonstrate that ZBP1-mediated PANoptosis contributes to the toxic effects of chemotherapeutic drugs, which is dependent on ZBP1 nucleic acid-binding activity. We found that ZBP1 expression is downregulated in tumor tissue. Furthermore, in colorectal cancer patients, dsRNA is induced by chemotherapy and sensed by ZBP1 in normal colonic tissues, suggesting ZBP1-mediated PANoptosis is activated by chemotherapy in normal tissues. Our findings indicate that ZBP1-mediated PANoptosis is activated by DNA damage and contributes to the toxic side effects of DNA-damage-based chemotherapy. These data suggest that ZBP1 could be a promising therapeutic target to alleviate chemotherapy-related side effects.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495893","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}

引用次数: 0

Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment. 代谢守门员：利用肿瘤衍生代谢物优化肿瘤微环境中基于 T 细胞的免疫疗法疗效。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-26 DOI: 10.1038/s41419-024-07122-6

Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui

{"title":"Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.","authors":"Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui","doi":"10.1038/s41419-024-07122-6","DOIUrl":"10.1038/s41419-024-07122-6","url":null,"abstract":"The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495888","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}

引用次数: 0

Impaired activation of succinate-induced type 2 immunity and secretory cell production in the small intestines of Ptk6-/- male mice. Ptk6-/- 雄性小鼠小肠中琥珀酸诱导的 2 型免疫激活和分泌细胞生成受损。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-26 DOI: 10.1038/s41419-024-07149-9

Katarina Vlajic, Wenjun Bie, Milica B Gilic, Angela L Tyner

{"title":"Impaired activation of succinate-induced type 2 immunity and secretory cell production in the small intestines of Ptk6-/- male mice.","authors":"Katarina Vlajic, Wenjun Bie, Milica B Gilic, Angela L Tyner","doi":"10.1038/s41419-024-07149-9","DOIUrl":"10.1038/s41419-024-07149-9","url":null,"abstract":"Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is distantly related to the SRC family of tyrosine kinases. It is expressed in epithelial linings and regulates regeneration and repair of the intestinal epithelium. Analysis of publicly available datasets showed Ptk6 is upregulated in tuft cells upon activation of type 2 immunity. We found that disruption of Ptk6 influences gene expression involved in intestinal immune responses. Administration of succinate, which mimics infection and activates tuft cells, revealed PTK6-dependent activation of innate immune responses in male but not female mice. In contrast to all wild type and Ptk6-/- female mice, Ptk6-/- male mice do not activate innate immunity or upregulate differentiation of the tuft and goblet secretory cell lineages following succinate treatment. Mechanistically, we found that PTK6 regulates Il25 and Irag2, genes that are required for tuft cell effector functions and activation of type 2 innate immunity, in organoids derived from intestines of male but not female mice. In patients with Crohn's disease, PTK6 is upregulated in tuft cells in noninflamed regions of intestine. These data highlight roles for PTK6 in contributing to sex differences in intestinal innate immunity and provide new insights into the regulation of IL-25.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516266","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}

引用次数: 0

Miro2 sulfhydration by CBS/H₂S promotes human trophoblast invasion and migration via regulating mitochondria dynamics. CBS/H2S的Miro2硫酸化作用通过调节线粒体动力学促进人类滋养细胞的侵袭和迁移。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-26 DOI: 10.1038/s41419-024-07167-7

Hao Feng, Zongxin Sun, Baoshi Han, Huitang Xia, Lumei Chen, Chunlei Tian, Suhua Yan, Yugen Shi, Jie Yin, Wengang Song, Peipei Gong, Shuanglian Wang, Yan Li

{"title":"Miro2 sulfhydration by CBS/H2S promotes human trophoblast invasion and migration via regulating mitochondria dynamics.","authors":"Hao Feng, Zongxin Sun, Baoshi Han, Huitang Xia, Lumei Chen, Chunlei Tian, Suhua Yan, Yugen Shi, Jie Yin, Wengang Song, Peipei Gong, Shuanglian Wang, Yan Li","doi":"10.1038/s41419-024-07167-7","DOIUrl":"10.1038/s41419-024-07167-7","url":null,"abstract":"Insufficient cytotrophoblast (CTB) migration and invasion into the maternal myometrium leads to pregnancy related complications like Intra-uterus Growth Restriction (IUGR), and pre-eclampsia (PE). We previously found that hydrogen sulfide (H2S) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that H2S levels were lower in PE patients' plasma; H2S synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H2S donor, 1 µM) promoted CBS/H2S translocation onto mitochondria, preserved mitochondria functions, enhanced cell invasion and migration. CBS knockdown hindered the above functions which were rescued by GYY4137, indicating the vital roles of CBS/H2S signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2C185/C504) were highly sulfhydrated by H2S. Knockdown Miro2 or double mutation of Miro2C185/C504 to serine fragmented mitochondria, and inhibited cell invasion and migration which can't be rescued by H2S. The present study showed that human cytotrophoblast receives low dose H2S regulation; CBS/H2S sustained mitochondria functions via Miro2C185/C504 sulfhydration to enhance cytotrophoblast mobility. These findings established a new regulatory pathway for cytotrophoblast functions, and provided new targets for IUGR and PE.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495889","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}

引用次数: 0

One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma. 单碳介导的嘌呤合成是胶质母细胞瘤产生替莫唑胺耐药性的原因。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-25 DOI: 10.1038/s41419-024-07170-y

Kimia Ghannad-Zadeh, Alyona Ivanova, Megan Wu, Taylor M Wilson, Alyssa Lau, Robert Flick, David G Munoz, Sunit Das

{"title":"One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.","authors":"Kimia Ghannad-Zadeh, Alyona Ivanova, Megan Wu, Taylor M Wilson, Alyssa Lau, Robert Flick, David G Munoz, Sunit Das","doi":"10.1038/s41419-024-07170-y","DOIUrl":"https://doi.org/10.1038/s41419-024-07170-y","url":null,"abstract":"Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495890","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}

引用次数: 0

Retraction Note: Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma. 撤稿说明：伊德拉利西通过 AKT/FoxO3a 促进肝细胞癌中 Bim 依赖性凋亡。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-24 DOI: 10.1038/s41419-024-07162-y

Dan Yue, Xun Sun

引用次数: 0

Enhanced mGluR₅ intracellular activity causes psychiatric alterations in Niemann Pick type C disease. mGluR5 细胞内活性增强导致尼曼皮克 C 型病的精神改变。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-23 DOI: 10.1038/s41419-024-07158-8

Ana Toledano-Zaragoza, Violeta Enriquez-Zarralanga, Sara Naya-Forcano, Víctor Briz, Rocío Alfaro-Ruíz, Miguel Parra-Martínez, Daniel N Mitroi, Rafael Luján, José A Esteban, María Dolores Ledesma

{"title":"Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease.","authors":"Ana Toledano-Zaragoza, Violeta Enriquez-Zarralanga, Sara Naya-Forcano, Víctor Briz, Rocío Alfaro-Ruíz, Miguel Parra-Martínez, Daniel N Mitroi, Rafael Luján, José A Esteban, María Dolores Ledesma","doi":"10.1038/s41419-024-07158-8","DOIUrl":"https://doi.org/10.1038/s41419-024-07158-8","url":null,"abstract":"Niemann-Pick disease Type C (NPC) is caused by mutations in the cholesterol transport protein NPC1 leading to the endolysosomal accumulation of the lipid and to psychiatric alterations. Using an NPC mouse model (Npc1nmf164) we show aberrant mGluR5 lysosomal accumulation and reduction at plasma membrane in NPC1 deficient neurons. This phenotype was induced in wild-type (wt) neurons by genetic and pharmacological NPC1 silencing. Extraction of cholesterol normalized mGluR5 distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR5 was functionally active leading to enhanced mGluR-dependent long-term depression (mGluR-LTD) in Npc1nmf164 hippocampal slices. mGluR-LTD was lower or higher in Npc1nmf164 slices compared with wt when stimulated with non-membrane-permeable or membrane-permeable mGluR5 agonists, respectively. Oral treatment with the mGluR5 antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1nmf164 mice. Increased neuronal mGluR5 levels were found in an NPC patient. These results implicate mGluR5 alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495885","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}

引用次数: 0

VASH2 enhances KIF3C-mediated EGFR-endosomal recycling to promote aggression and chemoresistance of lung squamous cell carcinoma by increasing tubulin detyrosination. VASH2 通过增加微管蛋白的脱酪氨酸化，增强 KIF3C 介导的表皮生长因子受体-内体循环，从而促进肺鳞癌的侵袭性和化疗耐药性。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-23 DOI: 10.1038/s41419-024-07155-x

Jing Wang, Pengpeng Liu, Rui Zhang, Biyuan Xing, Guidong Chen, Lei Han, Jinpu Yu

{"title":"VASH2 enhances KIF3C-mediated EGFR-endosomal recycling to promote aggression and chemoresistance of lung squamous cell carcinoma by increasing tubulin detyrosination.","authors":"Jing Wang, Pengpeng Liu, Rui Zhang, Biyuan Xing, Guidong Chen, Lei Han, Jinpu Yu","doi":"10.1038/s41419-024-07155-x","DOIUrl":"https://doi.org/10.1038/s41419-024-07155-x","url":null,"abstract":"Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495894","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}

引用次数: 0

Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression. 肝细胞特异性 NR5A2 缺乏症可通过下调 ALDH1B1 的表达诱导热变态反应并加剧非酒精性脂肪性肝炎。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-10-23 DOI: 10.1038/s41419-024-07151-1

Rong Zhao, Zizhen Guo, Kaikai Lu, Qian Chen, Farooq Riaz, Yimeng Zhou, Luyun Yang, Xiaona Cheng, Litao Wu, Kexin Cheng, Lina Feng, Sitong Liu, Xiaodan Wu, Minghua Zheng, Chunyan Yin, Dongmin Li

{"title":"Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression.","authors":"Rong Zhao, Zizhen Guo, Kaikai Lu, Qian Chen, Farooq Riaz, Yimeng Zhou, Luyun Yang, Xiaona Cheng, Litao Wu, Kexin Cheng, Lina Feng, Sitong Liu, Xiaodan Wu, Minghua Zheng, Chunyan Yin, Dongmin Li","doi":"10.1038/s41419-024-07151-1","DOIUrl":"10.1038/s41419-024-07151-1","url":null,"abstract":"Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2HKO) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2HKO mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495886","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}

引用次数: 0