Cell Death Discovery最新文献

Nesprin-2 contains BH3-like motifs that can promote cell death. nesprin2含有bh3样基序，可促进细胞死亡。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-06-03 DOI: 10.1038/s41420-025-02534-5

Hila Zohar, Amit Kessel, Liora Lindenboim, Dang Nguyen, Nir Ben-Tal, Gregg G Gundersen, Howard J Worman, David W Andrews, Reuven Stein

{"title":"Nesprin-2 contains BH3-like motifs that can promote cell death.","authors":"Hila Zohar, Amit Kessel, Liora Lindenboim, Dang Nguyen, Nir Ben-Tal, Gregg G Gundersen, Howard J Worman, David W Andrews, Reuven Stein","doi":"10.1038/s41420-025-02534-5","DOIUrl":"https://doi.org/10.1038/s41420-025-02534-5","url":null,"abstract":"BH3-only proteins are a subgroup of the pro-apoptotic Bcl-2 family proteins. They initiate apoptosis by interacting with the multidomain pro- and anti-apoptotic Bcl-2 family proteins. SYNE2 encodes multiple nesprin-2 (Nes2) isoforms of which the most abundant and the largest is the nuclear envelope protein nesprin-2 giant (Nes2G). Nes2G is a component of the nuclear envelope Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that connects the nucleus and the cytoskeleton. Previously, we showed that Nes2 has pro-apoptotic activity. We now show that Nes2G can bind multidomain pro-apoptotic and anti-apoptotic Bcl-2 family proteins and contains two BH3-like motifs near its N- and C-termini. Molecular modeling predicts that these BH3-like motifs have amphipathic α-helix structures and can dock onto the canonical groove of Bax and anti-apoptotic proteins as well as the trigger site of Bax. A chimeric tBid with its BH3 domain replaced with the C-terminal Nes2 BH3-like domain binds to Bax in cells. Furthermore, Nes2 BH3-like motif-containing fragments from the N- and the C-termini bind both pro-apoptotic and anti-apoptotic Bcl-2 proteins and promote cytochrome c release (indicative of apoptosis). Our results suggest that Nes2 acts as a BH3-only protein that regulates apoptosis by binding to the multidomain Bcl-2 family proteins.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"263"},"PeriodicalIF":6.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

LEADR, a p63 target, dampens interferon signalling in bladder cancer. p63靶点LEADR抑制膀胱癌中的干扰素信号传导。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-06-03 DOI: 10.1038/s41420-025-02546-1

Damiano Barnaba, Mariacristina Franzese Canonico, Manuela Helmer-Citterich, Paolo Gandellini, Gerry Melino, Artem Smirnov, Eleonora Candi

{"title":"LEADR, a p63 target, dampens interferon signalling in bladder cancer.","authors":"Damiano Barnaba, Mariacristina Franzese Canonico, Manuela Helmer-Citterich, Paolo Gandellini, Gerry Melino, Artem Smirnov, Eleonora Candi","doi":"10.1038/s41420-025-02546-1","DOIUrl":"https://doi.org/10.1038/s41420-025-02546-1","url":null,"abstract":"Bladder cancer affects over half a million people worldwide each year. Recent advances in early detection allowed a successful management of non-aggressive cancers, yet the recurrence rate remains high. Aggressive muscle-invasive bladder tumours are life-threatening and challenging to cure. Therefore, understanding of key molecular pathways involved in cancer progression is critical for developing of new personalised targeted therapies. Recently, non-coding RNAs (ncRNAs) have emerged as key regulators orchestrating complex biological processes in cancer, yet their function is not fully understood. Here, we compare non-muscle invasive and muscle invasive cell lines and identify a ncRNA gene MIR205HG and its transcript LEADR among the top ncRNAs downregulated in muscle invasive urothelial tumours. We show that LEADR expression is epigenetically regulated by master transcription factor p63. LEADR is localised in the nuclei of non-muscle invasive bladder cancer cells where it dampens hyperactivation of interferon stimulated genes possibly increasing sensitivity of bladder cancer cells to interferon signalling. These findings uncover an anti-tumoral role of non-coding RNA LEADR in mediating immune response in bladder cancer.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"264"},"PeriodicalIF":6.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

RGS3 acts as a tumor promoter by facilitating the regulation of the TGF-β signaling pathway and promoting EMT in ovarian cancer. RGS3在卵巢癌中作为肿瘤启动子，通过促进TGF-β信号通路的调节，促进EMT的发生。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-06-02 DOI: 10.1038/s41420-025-02536-3

Zizhao Wang, Huating Sun, Shunpeng Zhu, Fang Wang, Quan Li, Jinhua Zhou

{"title":"RGS3 acts as a tumor promoter by facilitating the regulation of the TGF-β signaling pathway and promoting EMT in ovarian cancer.","authors":"Zizhao Wang, Huating Sun, Shunpeng Zhu, Fang Wang, Quan Li, Jinhua Zhou","doi":"10.1038/s41420-025-02536-3","DOIUrl":"https://doi.org/10.1038/s41420-025-02536-3","url":null,"abstract":"Ovarian cancer (OC) is one of the most common and lethal solid malignancies among women, with its incidence steadily rising. Despite substantial advancements in OC research, its pathogenesis remains largely elusive. Recent studies indicate that the regulator of G protein signaling 3 (RGS3) is implicated in tumorigenesis, however, its specific role in OC development has not been extensively investigated. Herein, this research elucidated that the overexpression of RGS3 in OC correlates with adverse clinical pathological features and tumor progression. Furthermore, we demonstrated that silencing RGS3 promotes apoptosis, effectively inhibiting tumor growth and metastasis. Additionally, our findings reveal that RGS3 enhances oncogenic activity by participating in the regulation of the transforming growth factor-beta (TGF-β) pathway and corresponding epithelial-mesenchymal transition (EMT). The in-depth mechanism lies in the RGS3 facilitating the phosphorylation of SMAD2/3 by directly interacting with AT-rich interactive domain-containing protein 3B (ARID3B), which ultimately drives OC cell proliferation and metastasis. Therefore, our results position RGS3 as a significant prognostic biomarker and tumor-promoting factor in OC, underscoring the pivotal role of the RGS3/TGF-β/EMT signaling pathway in the pathogenesis of this malignancy.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"262"},"PeriodicalIF":6.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Combined inhibition by PRMT5 and MAT2A demonstrates a strong synthetic lethality in MTAP homozygous-deficient glioma models. PRMT5和MAT2A的联合抑制在MTAP纯合子缺陷胶质瘤模型中显示出很强的合成致死率。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-05-31 DOI: 10.1038/s41420-025-02545-2

Zuoyu Jiang, Xuetao Li, Zongyu Xiao, Wenjuan Gan, Xuewen Zhang, Yang Zhang, Weichao Wang, Qinzhi E, Yu Huang, Qikun Shi, Yi Tang, Jiaming Du, Hanmiao Dong, Jian Li, Yulun Huang

{"title":"Combined inhibition by PRMT5 and MAT2A demonstrates a strong synthetic lethality in MTAP homozygous-deficient glioma models.","authors":"Zuoyu Jiang, Xuetao Li, Zongyu Xiao, Wenjuan Gan, Xuewen Zhang, Yang Zhang, Weichao Wang, Qinzhi E, Yu Huang, Qikun Shi, Yi Tang, Jiaming Du, Hanmiao Dong, Jian Li, Yulun Huang","doi":"10.1038/s41420-025-02545-2","DOIUrl":"10.1038/s41420-025-02545-2","url":null,"abstract":"The intra- and intertumoral heterogeneity of gliomas present major challenges to effective chemotherapy. This study explored the combined effects of PRMT5 and MAT2A inhibitors on glioma progression. The expression of drug targets was determined in cell models using western blotting and immunofluorescence assay. CCK-8, colony-formation, EdU fluorescence, and flow cytometry cell cycle assays were conducted to assess the effect of the drugs on cell proliferation. Additionally, TUNEL fluorescence assay, flow cytometry apoptosis assay, western blotting, and comet assay were used to evaluate drug-induced apoptosis and DNA damage. Immunohistochemistry was used to validate the effect of the drugs in a 3D glioma organoid model. Patient-derived orthotopic xenograft models were used for in vivo efficacy evaluations. Lastly, transcriptome sequencing was used to elucidate the mechanism of action of the drugs, which was confirmed using western blotting. In phenotypic experiments, PRMT5 inhibitors reduced SDMA levels, inhibited cell proliferation, and promoted apoptosis in glioma models. The combination of PRMT5 inhibitors with MAT2A inhibitors enhanced synthetic lethality, leading to more potent antitumor effects. In vivo studies demonstrated that the drug combination significantly inhibited tumor growth and prolonged survival time. Our study proved the combination of PRMT5 and MAT2A inhibitors may induce synthetic lethality by downregulating the PI3K-AKT pathway, indicating the potential of this approach in treating gliomas.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"261"},"PeriodicalIF":6.1,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191564","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

Melanoma innervation, noradrenaline and cancer progression in zebrafish xenograft model. 斑马鱼异种移植模型中黑色素瘤神经支配、去甲肾上腺素与肿瘤进展。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-05-31 DOI: 10.1038/s41420-025-02523-8

Francesca Lorenzini, Johanna Marines, Julien Le Friec, Nam Do Khoa, Maria Angela Nieto, Berta Sanchez-Laorden, Maria Caterina Mione, Laura Fontenille, Karima Kissa

引用次数: 0

Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy. 常染色体显性视神经萎缩中OPA1突变的病理生理机制对比。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-05-30 DOI: 10.1038/s41420-025-02442-8

Shi-Qi Yao, Jia-Jian Liang, Hui Zhou, Shaoying Tan, Yingjie Cao, Chong-Bo Chen, Ciyan Xu, Ruixi Wang, Tai-Ping Li, Fang-Fang Zhao, Yun Wang, Han-Jie He, Dan Zhang, Meng Wang, Lifang Liu, Patrick Yu-Wai-Man, Shihui Wei, Ling-Ping Cen

{"title":"Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.","authors":"Shi-Qi Yao, Jia-Jian Liang, Hui Zhou, Shaoying Tan, Yingjie Cao, Chong-Bo Chen, Ciyan Xu, Ruixi Wang, Tai-Ping Li, Fang-Fang Zhao, Yun Wang, Han-Jie He, Dan Zhang, Meng Wang, Lifang Liu, Patrick Yu-Wai-Man, Shihui Wei, Ling-Ping Cen","doi":"10.1038/s41420-025-02442-8","DOIUrl":"10.1038/s41420-025-02442-8","url":null,"abstract":"Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"259"},"PeriodicalIF":6.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186656","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

Unveiling the nexus between environmental exposures and testicular damages: revelations from autophagy and oxidative stress imbalance. 揭示环境暴露与睾丸损伤之间的关系：自噬和氧化应激失衡的启示。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-05-29 DOI: 10.1038/s41420-025-02543-4

Xiuwen Kong, Xinda Wang, Qiushi Xia, Qingqing Hu, Wenqian Yu, Qiuru Huang, Jiaxin Li, Chenyu Wang, Ziwen Lin, Yiheng Liu, Yujuan Qi, Xiaofang Tan, Bo Zheng, Jun Yu

{"title":"Unveiling the nexus between environmental exposures and testicular damages: revelations from autophagy and oxidative stress imbalance.","authors":"Xiuwen Kong, Xinda Wang, Qiushi Xia, Qingqing Hu, Wenqian Yu, Qiuru Huang, Jiaxin Li, Chenyu Wang, Ziwen Lin, Yiheng Liu, Yujuan Qi, Xiaofang Tan, Bo Zheng, Jun Yu","doi":"10.1038/s41420-025-02543-4","DOIUrl":"10.1038/s41420-025-02543-4","url":null,"abstract":"Recent evidence consolidates the deleterious impact of environmental exposure on testicular damage. Environmental exposures can instigate testicular toxicity, causing damage to the Sertoli-Sertoli cell-mediated blood-testis barrier (BTB) integrity, alterations in hormone levels orchestrated by aberrant Leydig cells, and disruption of spermatogenesis. Despite diverse study designs and methodologies, a consensus is emerging on how environmental factors induce oxidative stress by elevating ROS levels, affecting autophagy through pathways such as the ROS-mediated mTOR signaling pathway, ultimately culminating in testicular damage. This review synthesizes existing literature on how environmental exposures, including metals, air pollutants, industrial contaminants, and pesticides, disturb testicular homeostasis via autophagy-mediated oxidative stress, highlighting recent significant advancements. It also explores interventions like antioxidant support and autophagy regulation to alleviate testicular damage. These findings underscore the importance of elucidating the mechanisms of autophagy influenced by environmental exposures in disrupting the equilibrium of oxidative stress, identifying potential drug targets, and establishing a groundwork for enhancing future treatments and clinical management of testicular injuries.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"258"},"PeriodicalIF":6.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180785","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

Artemisinin derivatives differently affect cell death of lung cancer subtypes by regulating GPX4 in patient-derived tissue cultures. 在患者来源的组织培养中，青蒿素衍生物通过调节GPX4不同程度地影响肺癌亚型细胞死亡。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-05-28 DOI: 10.1038/s41420-025-02537-2

Johanna Mölleken, Angelique Kragl, Astrid Monecke, Isabella Metelmann, Sebastian Krämer, Sonja Kallendrusch

{"title":"Artemisinin derivatives differently affect cell death of lung cancer subtypes by regulating GPX4 in patient-derived tissue cultures.","authors":"Johanna Mölleken, Angelique Kragl, Astrid Monecke, Isabella Metelmann, Sebastian Krämer, Sonja Kallendrusch","doi":"10.1038/s41420-025-02537-2","DOIUrl":"10.1038/s41420-025-02537-2","url":null,"abstract":"Resistant tumor cell populations are common after cytostatic drugs treatment. To overcome resistance mechanisms artemisinin derivatives, known for its complementary use during cancer treatement and ferroptosis induction, were investigated both as single agents and in combination with cisplatin (3 µM) in a complex organotypic tissue model of non-small cell lung cancer (NSCLC) patient samples. All substances-artemisinin (ART, 100 µM), artemether (ATM, 50 µM), artesunate (ATS, 20 µM), and dihydroartemisinin (DHA, 10 µM)-showed beneficial effects in most of the investigated patient-derived tissue cultures (PDTC). Tumor proliferation was reduced by DHA and ATS in both, standalone treatment and in combination with cisplatin, surpassing the efficacy of single cisplatin supplementation. In combination with cisplatin tumor apoptosis increased in most of lung squamous cell carcinoma (LUSC) PDTC, but not in lung adenocarcinoma (LUAD). The enzyme GPX4, inhibiting ferroptosis was up-regulated in LUAD but not in LUSC. Taken together, in the complex PDTC model system, LUSC displayed a higher sensitivity to ART derivatives, due to the lack of GPX4-mediated resistance to ferroptosis.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"256"},"PeriodicalIF":6.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172876","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

NOXA exacerbates endoplasmic-reticulum-stress-induced intervertebral disc degeneration by activating apoptosis and ECM degradation. NOXA通过激活细胞凋亡和ECM降解加剧内质网应力诱导的椎间盘退变。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-05-28 DOI: 10.1038/s41420-025-02539-0

Zhiming Liu, Hui Lu, Xianjuan Zhang, Shuai Tang, Antao Lin, Shuo Han, Xuexiao Ma

{"title":"NOXA exacerbates endoplasmic-reticulum-stress-induced intervertebral disc degeneration by activating apoptosis and ECM degradation.","authors":"Zhiming Liu, Hui Lu, Xianjuan Zhang, Shuai Tang, Antao Lin, Shuo Han, Xuexiao Ma","doi":"10.1038/s41420-025-02539-0","DOIUrl":"10.1038/s41420-025-02539-0","url":null,"abstract":"Intervertebral disc degeneration (IVDD) is a prevalent condition leading to low back pain. Endoplasmic reticulum stress (ERS) is strongly linked to IVDD progression, although the underlying mechanisms remain unclear. In this study, we investigated the effects of NOXA on ERS-induced IVDD. Primary nucleus pulposus cells (NPCs) were stimulated with Thapsigargin to mimic the ERS microenvironment in IVDD. Western blot analysis, PCR, immunofluorescence, and immunohistochemistry assay were performed to measure the expression levels of PERK, NOXA, and cell apoptosis- and extracellular-matrix-degradation-relevant proteins. JC-1 fluorescent probes, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and flow cytometry were used to measure mitochondrial function and apoptosis in NPCs under ERS conditions. Magnetic resonance imaging, Safranin O staining, alcian blue staining, and immunohistochemistry were performed to estimate the effects of NOXA knockdown on acupuncture-mediated IVDD in rats at both imaging and histological levels. The results showed that ERS induced and activated the PERK pathway during IVDD development. Mechanically, ERS induced NPC apoptosis and ECM degradation by upregulating PERK expression and activating NOXA expression. The genetic overexpression of NOXA inhibited cell proliferation and increased apoptosis, whereas its knockdown decreased MCL-1 expression and alleviated IVDD degeneration in human NPCs and rat models. NOXA plays a crucial role in the PERK/NOXA/MCL-1 axis, mediating the link between ERS and IVDD. Targeting NOXA expression may be an effective method for treating IVDD, laying the foundation for future research on molecular mechanisms and the development of new therapies.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"257"},"PeriodicalIF":6.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172880","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

CO confers neuroprotection via activating the PERK-calcineurin pathway and inhibiting necroptosis. 一氧化碳通过激活钙调磷酸酶-钙调磷酸酶通路和抑制坏死性下垂来提供神经保护。

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-05-27 DOI: 10.1038/s41420-025-02530-9

Jeongmin Park, LiHua Jin, Hyun-Chul Song, Yingqing Chen, Eun Young Jang, Gyu Hwan Park, Chae Ha Yang, Stefan W Ryter, Jeong Woo Park, Min Zheng, Yeonsoo Joe, Hun Taeg Chung

{"title":"CO confers neuroprotection via activating the PERK-calcineurin pathway and inhibiting necroptosis.","authors":"Jeongmin Park, LiHua Jin, Hyun-Chul Song, Yingqing Chen, Eun Young Jang, Gyu Hwan Park, Chae Ha Yang, Stefan W Ryter, Jeong Woo Park, Min Zheng, Yeonsoo Joe, Hun Taeg Chung","doi":"10.1038/s41420-025-02530-9","DOIUrl":"10.1038/s41420-025-02530-9","url":null,"abstract":"Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are marked by progressive neuronal loss. Regulated cell death programs (i.e., necroptosis) as well as homeostatic mechanisms (i.e., autophagy) can modulate disease pathogenesis. Low-dose carbon monoxide (CO) has been shown to activate cytoprotective responses in various models of tissue injury. Our study investigates the protective roles of CO in neurodegenerative disease through the modulation of necroptosis and autophagy programs. We found that CO activates the Protein kinase RNA (PKR)-like ER kinase (PERK) branch of the unfolded protein response (UPR) and the calcineurin pathway, leading to significant neuroprotective effects in cellular and mouse models of PD. CO-induced PERK activation promotes the nuclear translocation of transcription factor EB (TFEB). Subsequently, TFEB enhances autophagy through increased expression of autophagy-related genes and inhibits necroptosis by suppressing the phosphorylation and oligomerization of Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL), a key necroptosis regulator. Furthermore, CO enhances the expression of Beclin 1, which inhibits necroptosis, independently of its autophagic function, by regulating MLKL oligomerization. Our findings suggest that modulation of the PERK-calcineurin pathway and downstream activation of cellular defense mechanisms by CO may serve as a promising therapeutic approach to mitigate neuronal loss in neurodegenerative diseases.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"254"},"PeriodicalIF":6.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156741","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