Cell Death & Disease最新文献_第3页

MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07193-5

Zhengmeng Yang, Nan Hou, Wenxiang Cheng, Xuan Lu, Ming Wang, Shanshan Bai, Yuejun Lin, Yaofeng Wang, Sien Lin, Peng Zhang, Micky D Tortorella, Lu Feng, Gang Li

{"title":"MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress.","authors":"Zhengmeng Yang, Nan Hou, Wenxiang Cheng, Xuan Lu, Ming Wang, Shanshan Bai, Yuejun Lin, Yaofeng Wang, Sien Lin, Peng Zhang, Micky D Tortorella, Lu Feng, Gang Li","doi":"10.1038/s41419-024-07193-5","DOIUrl":"https://doi.org/10.1038/s41419-024-07193-5","url":null,"abstract":"Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378high) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"910"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853257","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}

引用次数: 0

NIR-715 photodynamic therapy induces immunogenic cancer cell death by enhancing the endoplasmic reticulum stress response.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07283-4

Zhen-Yuan Zheng, Wan Lin, Jia-Wan Su, Qing-Feng Huang, Cong Zhang, Wen-Xing Pan, En-Min Li, He-Feng Zhang, Li-Yan Xu

{"title":"NIR-715 photodynamic therapy induces immunogenic cancer cell death by enhancing the endoplasmic reticulum stress response.","authors":"Zhen-Yuan Zheng, Wan Lin, Jia-Wan Su, Qing-Feng Huang, Cong Zhang, Wen-Xing Pan, En-Min Li, He-Feng Zhang, Li-Yan Xu","doi":"10.1038/s41419-024-07283-4","DOIUrl":"https://doi.org/10.1038/s41419-024-07283-4","url":null,"abstract":"Effectively interfering with endoplasmic reticulum (ER) function in tumor cells and simultaneously activating an anti-tumor immune microenvironment to attack the tumor cells are promising strategies for cancer treatment. However, precise ER-stress induction is still a huge challenge. In this study, we synthesized a near-infrared (NIR) probe, NIR-715, which induces tumor cell death and inhibits tumor growth without causing apparent side effects. NIR-715 triggers severe ER stress and immunogenic cell death (ICD) after visible light exposure. NIR-715 induced ICD-associated HMGB1 release in vitro and anti-tumor immune responses, including increased cytotoxic T lymphocyte (GZMB+ CD8+ T cell) infiltration and decreased numbers of exhausted T lymphocytes (PD-L1+ CD8+ T cell). These findings suggest that NIR-715 may be a novel agent for \"cold\" tumor photodynamic therapy (PDT). Schematic illustration of NIR-715 photodynamic therapy for visible light-triggered, endoplasmic reticulum-targeting antitumor therapy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"890"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853259","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}

引用次数: 0

CPNE7 promotes colorectal tumorigenesis by interacting with NONO to initiate ZFP42 transcription.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07288-z

Liangbo Zhao, Xiao Sun, Chenying Hou, Yanmei Yang, Peiwen Wang, Zhaoyuan Xu, Zhenzhen Chen, Xiangrui Zhang, Guanghua Wu, Hong Chen, Hao Xing, Huimin Xie, Luyun He, Shuiling Jin, Benyu Liu

{"title":"CPNE7 promotes colorectal tumorigenesis by interacting with NONO to initiate ZFP42 transcription.","authors":"Liangbo Zhao, Xiao Sun, Chenying Hou, Yanmei Yang, Peiwen Wang, Zhaoyuan Xu, Zhenzhen Chen, Xiangrui Zhang, Guanghua Wu, Hong Chen, Hao Xing, Huimin Xie, Luyun He, Shuiling Jin, Benyu Liu","doi":"10.1038/s41419-024-07288-z","DOIUrl":"https://doi.org/10.1038/s41419-024-07288-z","url":null,"abstract":"Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death globally. Also, there is still a lack of effective therapeutic strategies for CRC patients owing to a poor understanding of its pathogenesis. Here, we analysed differentially expressed genes in CRC and identified CPNE7 as a novel driver of colorectal tumorigenesis. CPNE7 is highly expressed in CRC and negatively correlated with patients' prognosis. Upregulation of CPNE7 promotes proliferation and metastasis of cancer cells in vitro and in vivo, and vice versa. Mechanistically, CPNE7 interacts with NONO to initiate ZFP42 transcription, thus promoting CRC progression. Moreover, ZFP42 knockdown inhibits tumor cell proliferation and migration while promoting apoptosis. Notably, delivery of CPNE7 shRNA or the small molecule gramicidin, which blocks the interaction between CPNE7 and NONO, hinders tumor growth in vivo. In conclusion, our findings demonstrate that the CPNE7-NONO-ZFP42 axis promotes colorectal tumorigenesis and may be a new potential therapeutic target.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"896"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853150","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}

引用次数: 0

Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07274-5

Zengzhuang Yuan, Xinyan Han, Manyu Xiao, Taoyu Zhu, Yaping Xu, Qian Tang, Chen Lian, Zijin Wang, Junming Li, Boyu Wang, Changhui Li, Xiaochen Xiang, Ruobai Jin, Yufei Liu, Xinyu Yu, Kehang Zhang, Songsong Li, Madhumita Ray, Rong Li, Artiom Gruzdev, Shiqun Shao, Fangwei Shao, Hua Wang, Wang Lian, Yong Tang, Di Chen, Ying Lei, Xuru Jin, Qinglin Li, Weiwen Long, Huaqiong Huang, Francesco J DeMayo, Jian Liu

{"title":"Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis.","authors":"Zengzhuang Yuan, Xinyan Han, Manyu Xiao, Taoyu Zhu, Yaping Xu, Qian Tang, Chen Lian, Zijin Wang, Junming Li, Boyu Wang, Changhui Li, Xiaochen Xiang, Ruobai Jin, Yufei Liu, Xinyu Yu, Kehang Zhang, Songsong Li, Madhumita Ray, Rong Li, Artiom Gruzdev, Shiqun Shao, Fangwei Shao, Hua Wang, Wang Lian, Yong Tang, Di Chen, Ying Lei, Xuru Jin, Qinglin Li, Weiwen Long, Huaqiong Huang, Francesco J DeMayo, Jian Liu","doi":"10.1038/s41419-024-07274-5","DOIUrl":"https://doi.org/10.1038/s41419-024-07274-5","url":null,"abstract":"Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SCL7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SCL7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SCL7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SCL7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SCL7A11 expression levels were negatively associated with lung cancer patients' survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"897"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851901","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}

引用次数: 0

Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07272-7

Josephina Sampson, Hyun-Min Ju, Nan Zhang, Sharon Yeoh, Jene Choi, Richard Bayliss

{"title":"Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.","authors":"Josephina Sampson, Hyun-Min Ju, Nan Zhang, Sharon Yeoh, Jene Choi, Richard Bayliss","doi":"10.1038/s41419-024-07272-7","DOIUrl":"10.1038/s41419-024-07272-7","url":null,"abstract":"The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"912"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852995","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}

引用次数: 0

PGRN protects against serum deprivation-induced cell death by promoting the ROS scavenger system in cervical cancer.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07233-0

Tingting Feng, Xiaoying Xu, Xiao Wang, Wei Tang, Yi Lu

{"title":"PGRN protects against serum deprivation-induced cell death by promoting the ROS scavenger system in cervical cancer.","authors":"Tingting Feng, Xiaoying Xu, Xiao Wang, Wei Tang, Yi Lu","doi":"10.1038/s41419-024-07233-0","DOIUrl":"https://doi.org/10.1038/s41419-024-07233-0","url":null,"abstract":"Progranulin (PGRN), an autocrine growth factor with tumorigenic roles in a variety of tumors, is a putative survival factor for normal and cancer cells in vitro. However, the fundamental mechanism of PGRN-mediated survival of cancer cells suffering from various types of microenvironmental stresses, such as serum deprivation, remains unknown. We show here that serum deprivation decreases intracellular PGRN protein levels in cervical cancer cells. PGRN protects cervical cancer cells against serum deprivation-induced apoptosis, limits reactive oxygen species (ROS) levels, maintains mitochondria integrity, and reduces oxidative damage of protein, lipid and DNA. PGRN enhances the ROS scavenger system, as evidenced by increased superoxide dismutase (SOD), catalase protein expression and activity, elevated GSH and NADPH levels and increased phase II detoxification enzyme expression in cervical cancer cells after serum withdrawal. The role of PGRN in ROS clearance is mediated by the PGRN-stimulated nuclear factor erythroid-derived 2-like 2 (NFE2L2)-antioxidant response element (ARE) pathway. Our study reveals an antioxidant role of PGRN in supporting the survival of cervical cancer cells under oxidative stress. This insight provides a new perspective on the how cervical cancer cells adapt to microenvironmental stress, contributing to cell viability and other malignant characteristics.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"889"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852930","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}

引用次数: 0

Tipping the balance of cell death: alternative splicing as a source of MCL-1S in cancer.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07307-z

Mariusz L Hartman

{"title":"Tipping the balance of cell death: alternative splicing as a source of MCL-1S in cancer.","authors":"Mariusz L Hartman","doi":"10.1038/s41419-024-07307-z","DOIUrl":"https://doi.org/10.1038/s41419-024-07307-z","url":null,"abstract":"Apoptosis-regulating proteins from the B-cell lymphoma-2 (BCL-2) family are of continued interest as they represent promising targets for anti-cancer therapies. Myeloid cell leukemia-1 (MCL-1), which usually refers to the long isoform (MCL-1L) is frequently overexpressed in various types of cancer. However, MCL1 pre-mRNA can also undergo alternative splicing through exon skipping to yield the short isoform, MCL-1S. Regarding its structure and function, MCL-1S corresponds to BCL-2 homology domain 3 (BH3)-only pro-apoptotic proteins in contrast to the pro-survival role of MCL-1L. As cancer cells are usually characterized by the high MCL-1L:MCL-1S ratio, several studies revealed that overexpression of MCL-1S may constitute a new therapeutic approach in cancer and presumably overcome resistance to currently available drugs. Switching the balance towards high levels of MCL-1S is feasible by using inhibitors of alternative splicing-regulating proteins and strategies directly interfering with MCL1 pre-mRNA. Additionally, several compounds were shown to increase MCL-1S levels through unelucidated mechanisms, while diversely affecting the level of MCL-1L isoform. These mechanisms require detailed clarification as the balance between the long and short variants of MCL-1 can also contribute to mitochondrial hyperpolarization. In this respect, the role of MCL-1S in the regulation of apoptosis-unrelated events of the mitochondria physiology, including mitochondria fission and fusion also remains to be determined. In this review, the structure and function of MCL-1S isoform, and MCL-1S-targeting approaches are discussed.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"917"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852998","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}

引用次数: 0

miR-184, a downregulated ovary-elevated miRNA transcriptionally activated by SREBF2, exerts anti-apoptotic properties in ovarian granulosa cells through inducing SMAD3 expression.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07286-1

Baosen Shan, Yangan Huo, Zhennan Guo, Qiqi Li, Zengxiang Pan, Qifa Li, Xing Du

{"title":"miR-184, a downregulated ovary-elevated miRNA transcriptionally activated by SREBF2, exerts anti-apoptotic properties in ovarian granulosa cells through inducing SMAD3 expression.","authors":"Baosen Shan, Yangan Huo, Zhennan Guo, Qiqi Li, Zengxiang Pan, Qifa Li, Xing Du","doi":"10.1038/s41419-024-07286-1","DOIUrl":"https://doi.org/10.1038/s41419-024-07286-1","url":null,"abstract":"Follicular atresia is the primary threat to female fertility. miRNAs are dysregulated in granulosa cells (GCs) during follicular atresia, and have emerged as crucial regulators of the initiation and progression of follicular atresia. However, the downregulated ovary-elevated (OE) miRNAs and their biological functions in ovary remain elusive. Here, 13 downregulated OE miRNAs were systematically identified by integrating tissue expression high-throughput data and comparative transcriptome analyses, among which miR-184 was specifically highly expressed in ovary but dramatically downregulated during follicular atresia. Low miR-184 levels were also positively correlated with follicular atresia. Based on the in vitro GC and follicle culture system, we found that miR-184 suppressed GC apoptosis and follicular atresia. Mechanistically, miR-184 induced SMAD3 transcription by acting as a saRNA, and also stabilized SMAD3 mRNA by directly binding to its 5'-UTR, which promoted TGF-β pathway activity and its anti-apoptotic effect. In addition, miR-184 was transcribed independently of host gene, which was activated by SREBF2 in an H3K4me3-dependent manner. Comparative analysis revealed that SREBF2 expression and H3K4me3 enrichment on miR-184 promoter in GCs from atretic follicles were dramatically reduced, which leads to the downregulation of miR-184 during follicular atresia. Moreover, the expression pattern, function, target, and regulatory mechanism of miR-184 among mammals are highly conserved and universal. Taken together, our findings demonstrate that miR-184, transcriptionally activated by SREBF2 in an H3K4me3-dependent manner, exerts anti-atretic effects by inducing SMAD3 expression, highlighting that it is a promising regulator for improving follicular development, ovarian health and female fertility.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"892"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853255","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}

引用次数: 0

SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07282-5

Tingwen Gao, Zhenyang Guo, Xinyu Weng, Yikai Cui, Peng Li, Tao Hu, Wei Luo, Zheng Dong, Peng Wei, Yun Cai, Yijing Lu, Rifeng Gao, Hua Li, Xin Zhong, Junbo Ge

{"title":"SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation.","authors":"Tingwen Gao, Zhenyang Guo, Xinyu Weng, Yikai Cui, Peng Li, Tao Hu, Wei Luo, Zheng Dong, Peng Wei, Yun Cai, Yijing Lu, Rifeng Gao, Hua Li, Xin Zhong, Junbo Ge","doi":"10.1038/s41419-024-07282-5","DOIUrl":"https://doi.org/10.1038/s41419-024-07282-5","url":null,"abstract":"The macrophage-associated inflammation response plays an important role in myocardial ischemia-reperfusion injury (MIRI). SHEP1(SH2 domain-containing Eph receptor-binding protein 1) has been implicated in adhesion and migration of inflammatory cells. However, the role and molecular mechanism of SHEP1 regulating macrophage remains unclear during MIRI. Here, the expression of SHEP1 was increased in macrophages co-cultured with hypoxia-reoxygenated cardiomyocytes and within ischemia-reperfusion injured myocardium at the early stage of injury. Cell migration and inflammation were also enhanced in SHEP1 knock-out macrophages and macrophage-specific deficiency of SHEP1 mice under MIRI, which further led to deteriorated cardiac injury and cardiac function in vivo. Mechanistically, macrophage-derived SHEP1 competitively bound to G3BP1 to suppress inflammation via the MAPK pathway. In addition, administrating inhibitor of G3BP1 could improve cardiac function in macrophage-specific deficiency of SHEP1 mice under MIRI. Our results demonstrate that SHEP1 deficiency in macrophages exacerbates MIRI through G3BP1-dependent signaling pathway. SHEP1-G3BP1 interaction are therefore indispensable for SHEP1 regulated- infiltration and proinflammatory responses of macrophages, which provided a potential and clinically significant therapeutic target for MIRI.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"916"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852952","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}

引用次数: 0

Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-18 DOI: 10.1038/s41419-024-07231-2

Xin Su, Mi Bai, Yaqiong Shang, Yang Du, Shuang Xu, Xiuli Lin, Yunzhi Xiao, Yue Zhang, Huimei Chen, Aihua Zhang

{"title":"Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis.","authors":"Xin Su, Mi Bai, Yaqiong Shang, Yang Du, Shuang Xu, Xiuli Lin, Yunzhi Xiao, Yue Zhang, Huimei Chen, Aihua Zhang","doi":"10.1038/s41419-024-07231-2","DOIUrl":"https://doi.org/10.1038/s41419-024-07231-2","url":null,"abstract":"Acute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial carrier, as a potential target for AKI intervention. Renal Slc25a21 expression is negatively associated with kidney function in both AKI patients and cisplatin-induced murine models. Sustaining renal expression of Slc25a21 slowed down AKI progression by reducing cellular apoptosis, necroptosis, and the inflammatory response, likely through its regulation of 2-oxoadipate conversion. Slc25a21 is highly expressed in proximal tubular epithelial cells, and its down-regulation contributes to compromised mitochondrial biogenesis and integrity, as well as impaired oxidative phosphorylation. Mechanistically, reduced Slc25a21 in AKI disrupts mitochondrial 2-oxoadipate transport, affecting related metabolites influx and the tricarboxylic acid cycle. These findings demonstrate a previously unappreciated metabolic function of Slc25a21 in tubular cells, and suggest that targeting mitochondrial metabolic homeostasis by sustaining Slc25a21 expression could be a potential novel therapeutic strategy for AKI.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"891"},"PeriodicalIF":8.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853063","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}

引用次数: 0