Cell Death Discovery最新文献_第2页

CRAT downregulation promotes ovarian cancer progression by facilitating mitochondrial metabolism through decreasing the acetylation of PGC-1α. CRAT下调通过降低PGC-1α的乙酰化来促进线粒体代谢，从而促进卵巢癌的进展。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-19 DOI: 10.1038/s41420-025-02294-2

Zhen Zhang, Shuhua Zhao, Xiaohui Lv, Yan Gao, Qian Guo, Yanjie Ren, Yuanyuan He, Yihua Jin, Hong Yang, Shujuan Liu, Xiaohong Zhang

{"title":"CRAT downregulation promotes ovarian cancer progression by facilitating mitochondrial metabolism through decreasing the acetylation of PGC-1α.","authors":"Zhen Zhang, Shuhua Zhao, Xiaohui Lv, Yan Gao, Qian Guo, Yanjie Ren, Yuanyuan He, Yihua Jin, Hong Yang, Shujuan Liu, Xiaohong Zhang","doi":"10.1038/s41420-025-02294-2","DOIUrl":"https://doi.org/10.1038/s41420-025-02294-2","url":null,"abstract":"Mitochondrial dysfunctions are closely associated with different types of disease, including cancer. Carnitine acetyltransferase (CRAT) is a mitochondrial-localized enzyme catalyzing the reversible transfer of acyl groups from an acyl-CoA thioester to carnitine and regulates the ratio of acyl-CoA/CoA. Our bioinformatics analysis using public database revealed a significant decrease of CRAT expression in ovarian cancer (OC). However, the functions of CRAT have rarely been investigated in human cancers, especially in OC. Here, we found a frequent down-regulation of CRAT in OC, which is mainly caused by up-regulation of miR-132-5p. Downregulation of CRAT was significantly associated with shorter survival time for patients with OC. Forced expression of CRAT suppressed OC growth and metastasis by inducing cell cycle arrest and epithelial to mesenchymal transition (EMT). By contrast, CRAT knockdown promoted OC growth and metastasis. Mechanistically, we found that CRAT downregulation promoted OC growth and metastasis by increasing mitochondrial biogenesis to facilitate mitochondrial metabolism through reducing the acetylation of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α). In summary, CRAT functions as a critical tumor suppressor in OC progression by enhancing PGC-1α-mediated mitochondrial biogenesis and metabolism, suggesting CRAT as a potential therapeutic target in treatment of OC.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"15"},"PeriodicalIF":6.1,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000698","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}

引用次数: 0

Deciphering the mechanisms of long non-coding RNAs in ferroptosis: insights into its clinical significance in cancer progression and immunology. 解读长链非编码rna在铁下垂中的机制：洞察其在癌症进展和免疫学中的临床意义。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-18 DOI: 10.1038/s41420-025-02290-6

Shengming Ou, Xiaoya Nie, Xiangyu Qiu, Xin Jin, Geyan Wu, Rongxin Zhang, Jinrong Zhu

引用次数: 0

Helicobacter pylori reduces METTL14-mediated VAMP3 m⁶A modification and promotes the development of gastric cancer by regulating LC3C-mediated c-Met recycling. 幽门螺杆菌通过调节lc3c介导的c-Met再循环，降低mettl14介导的VAMP3 m6A修饰，促进胃癌的发生发展。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-18 DOI: 10.1038/s41420-025-02289-z

Xixi Cui, Mingjie Chang, Yuqiong Wang, Jiayi Liu, Zenghui Sun, Qiyu Sun, Yundong Sun, Juchao Ren, Wenjuan Li

{"title":"Helicobacter pylori reduces METTL14-mediated VAMP3 m6A modification and promotes the development of gastric cancer by regulating LC3C-mediated c-Met recycling.","authors":"Xixi Cui, Mingjie Chang, Yuqiong Wang, Jiayi Liu, Zenghui Sun, Qiyu Sun, Yundong Sun, Juchao Ren, Wenjuan Li","doi":"10.1038/s41420-025-02289-z","DOIUrl":"https://doi.org/10.1038/s41420-025-02289-z","url":null,"abstract":"Helicobacter pylori (H. pylori) plays an important role in the malignant transformation of the gastric mucosa from chronic inflammation to cancer. However, the mechanisms underlying the epigenetic regulation of gastric carcinogenesis mediated by H. pylori remain unclear. Here, we uncover that H. pylori inhibits METTL14 by upregulating ATF3. METTL14 inhibits gastric cancer (GC) cell proliferation and metastasis in vitro and in vivo. Downregulation of METTL14 inhibits Vesicle-associated membrane protein-3 (VAMP3) by reducing the m6A modification level of VAMP3 mRNA and the stability of IGF2BP2-dependent mRNA. H. pylori also accelerates the malignant progression of GC by regulating VAMP3/LC3C-mediated c-Met recycling. Moreover, the expression of METTL14 and VAMP3 in Hp+ chronic gastritis tissues is much lower than that in Hp- chronic gastritis tissues. METTL14 and VAMP3 expression levels are downregulated notably in cancerous tissues of patients with GC. Therefore, our results show a novel METTL14-VAMP3-LC3C-c-Met signalling axis in the GC development mediated by H. pylori infection, which reveals a novel m6A epigenetic modification mechanism for GC and provides potential prognostic biomarkers for GC progression.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"13"},"PeriodicalIF":6.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000714","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}

引用次数: 0

CDK14 regulates the development and repair of lung. CDK14调节肺的发育和修复。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-18 DOI: 10.1038/s41420-025-02292-4

Jian-Wei Chen, Yu-Xiang Wang, Rong-Rong Gao, Lan-Yue Ma, Jing Zhong, Jia-Xin Yang, Zhao-Hua Deng, Yu-Yan Li, Xiao-Ling Li, Ya-Hai Shu, Wen-Jing Guo, Zi-Yuan Zhou, Xiao Yu Tian, Jinjin Ma, Yang Liu, Qi Chen

{"title":"CDK14 regulates the development and repair of lung.","authors":"Jian-Wei Chen, Yu-Xiang Wang, Rong-Rong Gao, Lan-Yue Ma, Jing Zhong, Jia-Xin Yang, Zhao-Hua Deng, Yu-Yan Li, Xiao-Ling Li, Ya-Hai Shu, Wen-Jing Guo, Zi-Yuan Zhou, Xiao Yu Tian, Jinjin Ma, Yang Liu, Qi Chen","doi":"10.1038/s41420-025-02292-4","DOIUrl":"https://doi.org/10.1038/s41420-025-02292-4","url":null,"abstract":"Cyclin-dependent kinases (CDK) 14 regulates cell cycle, tumor expansion by influencing the downstream targets of the canonical Wnt signaling pathway. However, the function of CDK14 during organ development and regeneration has not been investigated in genetically-modified animals. Here, we found that genetic ablation of Cdk14 influenced pulmonary vascular endothelial cells and alveolar epithelial cells during mice embryonic development as well as repair of lung after bleomycin or lipopolysaccharide induced injury. Genetic knockout of Cdk14 and the CDK14 covalent inhibitor FMF-04-159-2 resulted in reduction of pulmonary vessel covered area and epithelial cell number, exhibiting increased mortality and more severe lung damage after injury. Mechanistically, Cdk14 ablation inhibited the proliferation of epithelial and vascular endothelial cells, inducing cell cycle arrest at the G2/M phase. Through RNA-seq analysis of both endothelial and epithelial cells, we found that knockdown of Cdk14 controls the expression of signal transducers and activator of transcription 1 (STAT1) as well as associated genes in interferon signaling. Disruption of Cdk14 interferes with IFN-γ induced lung repair in vivo, suggesting potential crosstalk of CDK14 signaling and IFN-γ pathway. Our work highlights the importance of Cdk14 in lung development and regenerative repair through an uncharacterized CDK14- IFN-γ signaling axis.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"12"},"PeriodicalIF":6.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000694","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}

引用次数: 0

pir-hsa-216911 inhibit pyroptosis in hepatocellular carcinoma by suppressing TLR4 initiated GSDMD activation. pir-hsa-216911通过抑制TLR4启动的GSDMD激活来抑制肝癌细胞的焦亡。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-17 DOI: 10.1038/s41420-024-02285-9

Zhouxiang Liao, Lichao Yang, Xiaojing Cheng, Xuejing Huang, Qi Zhang, Daoqiang Wen, Zhenyu Song, Yasi Li, Sha Wen, Yongfeng Li, Meizhen Ou, Zhangnan Huang, Tianqi Liu, Min He

{"title":"pir-hsa-216911 inhibit pyroptosis in hepatocellular carcinoma by suppressing TLR4 initiated GSDMD activation.","authors":"Zhouxiang Liao, Lichao Yang, Xiaojing Cheng, Xuejing Huang, Qi Zhang, Daoqiang Wen, Zhenyu Song, Yasi Li, Sha Wen, Yongfeng Li, Meizhen Ou, Zhangnan Huang, Tianqi Liu, Min He","doi":"10.1038/s41420-024-02285-9","DOIUrl":"https://doi.org/10.1038/s41420-024-02285-9","url":null,"abstract":"Hepatocellular carcinoma (HCC) is a global health concern, ranking as the fourth leading cause of cancer-related deaths worldwide. However, the role of piwi-interacting RNAs (piRNAs) in HCC processes has not been extensively explored. Through small RNA sequencing, our study identified a specific piRNA, pir-hsa-216911, which is highly expressed in HCC cells. This overexpression of pir-hsa-216911 promotes HCC cell invasion and inhibits cell death, particularly pyroptosis. Knocking out pir-hsa-216911 led to increased cell pyroptosis activity, resulting in the activation of caspase-1 and GSDMD. Further analysis revealed that pir-hsa-216911 targets and suppresses TLR4, a key gene associated with pyroptosis in HCC. In the Huh7 cell line, pir-hsa-216911 knockout confirmed its role in suppressing the TLR4/NFκB/NLRP3 pathway by silencing TLR4. Knocking out pir-hsa-216911 significantly inhibited the formation of Huh7 xenograft tumor. In HCC patients, pir-hsa-216911 was highly expressed in HCC tumor samples with steatosis, suppressing TLR4 expression and inhibiting GSDMD activation. This study introduces pir-hsa-216911 as a new high-expressing piRNA in HCC, which inhibits pyroptosis by silencing TLR4 to suppress GSDMD activation. These findings have significant implications for HCC molecular subtyping and as a potential target for cancer therapy.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"11"},"PeriodicalIF":6.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000762","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}

引用次数: 0

GILT stabilizes cofilin to promote the metastasis of prostate cancer. GILT稳定cofilin促进前列腺癌转移。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-16 DOI: 10.1038/s41420-025-02288-0

Dunsheng Han, Zhiming Wu, Cong Zhang, Ziwei Wei, Fan Chao, Xuefeng Xie, Jinke Liu, Yufeng Song, Xiaoming Song, Dingchang Shao, Shiyu Wang, Guoxiong Xu, Gang Chen

{"title":"GILT stabilizes cofilin to promote the metastasis of prostate cancer.","authors":"Dunsheng Han, Zhiming Wu, Cong Zhang, Ziwei Wei, Fan Chao, Xuefeng Xie, Jinke Liu, Yufeng Song, Xiaoming Song, Dingchang Shao, Shiyu Wang, Guoxiong Xu, Gang Chen","doi":"10.1038/s41420-025-02288-0","DOIUrl":"https://doi.org/10.1038/s41420-025-02288-0","url":null,"abstract":"Gamma-interferon-induced lysosomal thiol reductase (GILT), known for catalyzing disulfide bond reduction, is involved in various physiological processes. While the involvement of GILT in the development of various tumors has been demonstrated, the mechanisms underlying its regulation in prostate cancer (PCa) are not fully understood. In the present study, we confirmed that GILT was significantly upregulated in PCa and facilitated tumor metastasis. Mechanistically, GILT stabilized the cofilin protein by competitively binding to cofilin with Src family tyrosine kinase (SRC), inhibiting SRC-mediated tyrosine phosphorylation of cofilin, thereby suppressing the ubiquitination pathway degradation of cofilin. GILT overexpression stabilized and increased the protein level of cofilin in PCa cells and promoted the metastasis of PCa cells by accelerating actin dynamics through cofilin-mediated actin severing. Our findings reveal a novel mechanism of GILT in PCa and provide a new potential target for the diagnosis and treatment of PCa patients.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"10"},"PeriodicalIF":6.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000662","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}

引用次数: 0

IFNγ regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A. IFNγ通过DNMT3A抑制SPOCD1的表达来调节KFs中的铁下垂。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-16 DOI: 10.1038/s41420-024-02257-z

Xiuxia Wang, Yating Yang, Xianyu Zhou, Shun Yu, Xusong Luo, Lin Lu, Zhen Gao, Jun Yang

{"title":"IFNγ regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A.","authors":"Xiuxia Wang, Yating Yang, Xianyu Zhou, Shun Yu, Xusong Luo, Lin Lu, Zhen Gao, Jun Yang","doi":"10.1038/s41420-024-02257-z","DOIUrl":"https://doi.org/10.1038/s41420-024-02257-z","url":null,"abstract":"Keloid is benign skin tumor, and their curing is relatively difficult due to the unclear mechanism of formation. Inducing ferroptosis of keloid fibroblasts (KFs) may become a new method for treating keloid. Here, we discover interferon (IFN)γ could induce KFs ferroptosis through inhibiting SPOC domain-containing protein 1 (SPOCD1), serving as a mode of action for CD8+T cell (CTL)-mediated keloid killing. Mechanistically, keloid IFNγ deficiency in combination with reduced DNMT3A increase the expression of SPOCD1, thereby promoting KFs' proliferation and inhibiting its ferroptosis. Moreover, keloid SPOCD1 deficiency attenuates KFs progression and extracellular matrix (ECM) deposition. Reducing IFNγ and SPOCD1 simultaneously can increase the positive rate of reactive oxygen species (ROS) and promote mitochondrial shrinkage. Ex-vivo explant keloid culture has also confirmed that the reduction of SPOCD1 helps to reduce the proliferation rate of KFs, inhibit the angiogenesis of keloid scars, and thus inhibit keloid formation. Thus, IFNγ signaling paired with SPOCD1 is a natural keloid ferroptosis promoting mechanism and a mode of action of CTLs. Targeting SPOCD1 pathway is a potential anti-keloid approach.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"9"},"PeriodicalIF":6.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000743","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}

引用次数: 0

Mast cells: key players in digestive system tumors and their interactions with immune cells. 肥大细胞：消化系统肿瘤及其与免疫细胞相互作用的关键参与者。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-15 DOI: 10.1038/s41420-024-02258-y

Feihong Shu, Jie Yu, Youjia Liu, Fang Wang, Guoyou Gou, Min Wen, Chen Luo, Xianmin Lu, Yanxia Hu, Qian Du, Jingyu Xu, Rui Xie

{"title":"Mast cells: key players in digestive system tumors and their interactions with immune cells.","authors":"Feihong Shu, Jie Yu, Youjia Liu, Fang Wang, Guoyou Gou, Min Wen, Chen Luo, Xianmin Lu, Yanxia Hu, Qian Du, Jingyu Xu, Rui Xie","doi":"10.1038/s41420-024-02258-y","DOIUrl":"https://doi.org/10.1038/s41420-024-02258-y","url":null,"abstract":"Mast cells (MCs) are critical components of both innate and adaptive immune processes. They play a significant role in protecting human health and in the pathophysiology of various illnesses, including allergies, cardiovascular diseases and autoimmune diseases. Recent studies in tumor-related research have demonstrated that mast cells exert a substantial influence on tumor cell behavior and the tumor microenvironment, exhibiting both pro- and anti-tumor effects. Specifically, mast cells not only secrete mediators related to pro-tumor function such as trypsin-like enzymes, chymotrypsin, vascular endothelial cell growth factor and histamine, but also mediators related to anti-tumor progression such as cystatin C and IL-17F. This dual role of mast cells renders them an under-recognized but very promising target for tumor immunotherapy. Digestive system tumors, characterized by high morbidity and associated mortality rates globally, are increasingly recognized as a significant healthcare burden. This paper examines the influence of mast cell-derived mediators on the development of tumors in the digestive system. It also explores the prognostic significance of mast cells in patients with various gastrointestinal cancers at different stages of the disease. Additionally, the article investigates the interactions between mast cells and immune cells, as well as the potential relationships among intratumoral bacteria, immune cells, and mast cell within digestive system microenvironment. The aim is to propose new strategies for the immunotherapy of digestive system tumors by targeting mast cells.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"8"},"PeriodicalIF":6.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000679","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}

引用次数: 0

MiRNAs as major players in brain health and disease: current knowledge and future perspectives. mirna作为脑健康和疾病的主要参与者：当前的知识和未来的观点。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-13 DOI: 10.1038/s41420-024-02283-x

Sarika V Kapplingattu, Sujata Bhattacharya, Yogita K Adlakha

{"title":"MiRNAs as major players in brain health and disease: current knowledge and future perspectives.","authors":"Sarika V Kapplingattu, Sujata Bhattacharya, Yogita K Adlakha","doi":"10.1038/s41420-024-02283-x","DOIUrl":"10.1038/s41420-024-02283-x","url":null,"abstract":"MicroRNAs are regulators of gene expression and their dysregulation can lead to various diseases. MicroRNA-135 (MiR-135) exhibits brain-specific expression, and performs various functions such as neuronal morphology, neural induction, and synaptic function in the human brain. Dysfunction of miR-135 has been reported in brain tumors, and neurodegenerative and neurodevelopmental disorders. Several reports show downregulation of miR-135 in glioblastoma, indicating its tumor suppressor role in the pathogenesis of brain tumors. In this review, by performing in silico analysis of molecular targets of miR-135, we reveal the significant pathways and processes modulated by miR-135. We summarize the biological significance, roles, and signaling pathways of miRNAs in general, with a focus on miR-135 in different neurological diseases including brain tumors, and neurodegenerative and neurodevelopmental disorders. We also discuss methods, limitations, and potential of glioblastoma organoids in recapitulating disease initiation and progression. We highlight the promising therapeutic potential of miRNAs as antitumor agents for aggressive human brain tumors including glioblastoma.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"7"},"PeriodicalIF":6.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977633","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}

引用次数: 0

Developing novel Lin28 inhibitors by computer aided drug design. 利用计算机辅助药物设计开发新型Lin28抑制剂。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-12 DOI: 10.1038/s41420-024-02281-z

Victor M Matias-Barrios, Mariia Radaeva, Graciella Rosellinny, Qiongqiong Jia, Ning Xie, Monica Villanueva, Hanadi Ibrahim, Jason Smith, Martin Gleave, Nada Lallous, Suzana K Straus, Artem Cherkasov, Xuesen Dong

{"title":"Developing novel Lin28 inhibitors by computer aided drug design.","authors":"Victor M Matias-Barrios, Mariia Radaeva, Graciella Rosellinny, Qiongqiong Jia, Ning Xie, Monica Villanueva, Hanadi Ibrahim, Jason Smith, Martin Gleave, Nada Lallous, Suzana K Straus, Artem Cherkasov, Xuesen Dong","doi":"10.1038/s41420-024-02281-z","DOIUrl":"10.1038/s41420-024-02281-z","url":null,"abstract":"Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"5"},"PeriodicalIF":6.1,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969703","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}

引用次数: 0