Cell Death & Disease最新文献

{"title":"Hypermethylation of CDKN2A CpG island drives resistance to PRC2 inhibitors in SWI/SNF loss-of-function tumors.","authors":"Xinghao Wang, Yajun Wang, Min Xie, Shichao Ma, Yilin Zhang, Lele Wang, Yangfeng Ge, Guobin Li, Mengxi Zhao, Sheng Chen, Chenxi Yan, Hailong Zhang, Wei Sun","doi":"10.1038/s41419-024-07109-3","DOIUrl":"10.1038/s41419-024-07109-3","url":null,"abstract":"<p><p>Polycomb repressive complex 2 (PRC2) catalyzes the writing of the tri-methylated histone H3 at Lys27 (H3K27me3) epigenetic marker and suppresses the expression of genes, including tumor suppressors. The function of the complex can be partially antagonized by the SWI/SNF chromatin-remodeling complex. Previous studies have suggested that PRC2 is important for the proliferation of tumors with SWI/SNF loss-of-function mutations. In the present study, we have developed an EED-directed allosteric inhibitor of PRC2 termed BR0063, which exhibits anti-proliferative properties in a subset of solid tumor cell lines harboring mutations of the SWI/SNF subunits, SMARCA4 or ARID1A. Tumor cells sensitive to BR0063 exhibited several distinct phenotypes, including cell senescence, which was mediated by the up-regulation of CDKN2A/p16. Further experiments revealed that the expression of p16 was suppressed in the BR0063-resistant cells via DNA hypermethylation in the CpG island (CGI) promoter region, rather than via PRC2 occupancy. The expression of TET1, which is required for DNA demethylation, was found to be inversely correlated with p16 CGI methylation, and this may serve as a biomarker for the prediction of resistance to PRC2 inhibitors in SWI/SNF LOF tumors.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 11","pages":"794"},"PeriodicalIF":8.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582210","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}

{"title":"Author Correction: EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer.","authors":"Yiming He, Mingxi Gan, Yanan Wang, Tong Huang, Jianbin Wang, Tianyu Han, Bentong Yu","doi":"10.1038/s41419-024-07055-0","DOIUrl":"10.1038/s41419-024-07055-0","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 11","pages":"789"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575101","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}

{"title":"VCP enhances autophagy-related osteosarcoma progression by recruiting USP2 to inhibit ubiquitination and degradation of FASN.","authors":"Shijiang Wang, Jiangbo Nie, Haoxin Jiang, Anan Li, Nanshan Zhong, Weilai Tong, Geliang Yao, Alan Jiang, Xinsheng Xie, Yanxin Zhong, Zhiguo Shu, Jiaming Liu, Feng Yang, Zhili Liu","doi":"10.1038/s41419-024-07168-6","DOIUrl":"10.1038/s41419-024-07168-6","url":null,"abstract":"<p><p>Osteosarcoma (OS) is a highly aggressive malignant tumor with a high rate of disability and mortality rates, and dysregulated autophagy is a crucial factor in cancer. However, the molecular mechanisms that regulate autophagy in OS remain unclear. This study aimed to explore key molecules that affect autophagy in OS and their regulatory mechanisms. We found that fatty acid synthase (FASN) was significantly increased in activated autophagy models of OS and promoted OS proliferation in an autophagy-dependent manner, as detected by LC3 double-labeled fluorescence confocal microscopy, western blotting, transmission electron microscopy (TEM), and cell functional experiments. Furthermore, co-immunoprecipitation combined with mass spectrometry (Co-IP/MS), ubiquitination modification, molecular docking, and protein truncation methods were used to identify FASN-interacting proteins and analyze their effects on OS. Valosin-containing protein (VCP) enhanced the FASN stability by recruiting ubiquitin specific peptidase-2 (USP2) to remove the K48-linked ubiquitin chains from FASN; domain 2 of VCP and the amino acid sequence () of USP2 were critical for their interactions. Gain- and loss-of-function experiments showed that the inhibition of FASN or USP2 attenuated the stimulatory effect of VCP overexpression on autophagy and the malignant phenotypes of OS cells in vitro and in vivo. Notably, micro-CT indicated that VCP induced severe bone destruction in nude mice, which was abrogated by FASN or USP2 downregulation. In summary, VCP recruits USP2 to stabilize FASN by deubiquitylation, thereby activating autophagy and promoting OS progression. The identification of the VCP/USP2/FASN axis, which mediates autophagy regulation, provides important insights into the underlying mechanisms of OS and offers potential diagnostic and therapeutic strategies for patients with OS.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 11","pages":"788"},"PeriodicalIF":8.1,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567412","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}

{"title":"G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1.","authors":"Francisco Exposito, Miriam Redrado, Diego Serrano, Silvia Calabuig-Fariñas, Aida Bao-Caamano, Sandra Gallach, Eloisa Jantus-Lewintre, Angel Diaz-Lagares, Aitor Rodriguez-Casanova, Juan Sandoval, Edurne San Jose-Eneriz, Javier Garcia, Esther Redin, Yaiza Senent, Sergio Leon, Ruben Pio, Rafael Lopez, Julen Oyarzabal, Antonio Pineda-Lucena, Xabier Agirre, Luis M Montuenga, Felipe Prosper, Alfonso Calvo","doi":"10.1038/s41419-024-07156-w","DOIUrl":"10.1038/s41419-024-07156-w","url":null,"abstract":"<p><p>The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 11","pages":"787"},"PeriodicalIF":8.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564109","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}

{"title":"Inhibition of mitochondrial OMA1 ameliorates osteosarcoma tumorigenesis.","authors":"Lingyan Chen, Dejian Chen, Yiming Pan, Yimei Mo, Biyu Lai, Huiguang Chen, Da-Wei Zhang, Xiao-Dan Xia","doi":"10.1038/s41419-024-07127-1","DOIUrl":"10.1038/s41419-024-07127-1","url":null,"abstract":"<p><p>OMA1 is an ATP-independent zinc metalloprotease essential for maintaining mitochondrial homeostasis and plays a vital role in tumorigenesis. Depending on the type of cancer, a decrease in OMA1 expression has been linked to a varying prognosis for patients. The role of OMA1 in human osteosarcoma (OS), one of the most prevalent malignant bone tumors, remains elusive. Here, we observed elevated OMA1 expression in OS tumor tissues from four patients with advanced OS. Knockout of OMA1 in OS cells significantly reduces OS tumor weight and size, and lung metastatic nodules in BALB/c nude mice. Immunohistochemistry analysis showed a significant decrease in Ki67 and an increase in Cleaved-caspase 3 in OMA1 knockout tumor samples. Mechanistically, we found that OMA1 deficiency increases the levels of PINK1 and Parkin and consequently induces excessive mitophagy, leading to increased apoptosis and reduced cell proliferation and invasion in OS cells. Specifically, OMA1 deficiency reduces the amount of cytosolic p53 and p53-associated cytosolic Parkin but increases mitochondrial p53, which may lead to enhanced apoptosis. Regarding the effect on cell proliferation and invasion, loss of OMA1 reduces mitochondrial ROS levels and increases cytosolic glycogen synthase kinase 3β (GSK3β) levels, thereby increasing interaction between GSK3β and β-catenin and then reducing cytosolic and nuclear β-catenin. This contributes to reduced cell proliferation and migration in OMA1-deficient cells. Moreover, we found that ciclopirox (CPX), an antifungal drug, induces OMA1 self-cleavage and L-OMA1 degradation in cultured OS cells. CPX also reduces tumor development of control OS cells but not OMA1-deficient OS cells in mice. These findings strongly support the important role of OMA1 in OS tumorigenesis and suggest that OMA1 may be a valuable prognostic marker and a promising therapeutic target for OS.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 11","pages":"786"},"PeriodicalIF":8.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564116","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}

{"title":"Nicotine-induced CHRNA5 activation modulates CES1 expression, impacting head and neck squamous cell carcinoma recurrence and metastasis via MEK/ERK pathway.","authors":"Chen Feng, Wei Mao, Chenyang Yuan, Pin Dong, Yuying Liu","doi":"10.1038/s41419-024-07178-4","DOIUrl":"10.1038/s41419-024-07178-4","url":null,"abstract":"<p><p>The mucosal epithelium of the head and neck region (including the oral cavity, nasal cavity, pharynx, nasopharynx, and larynx) is the primary site exposed to tobacco smoke, and its presence of nicotinic acetylcholine receptors (nAChRs) has been observed in the mucosal epithelial cells of this area. It remains unclear whether HNSC cells can migrate and invade through nAChR signaling. A model of HNSC cells exposed to nicotine is established. Cell proliferation following nicotine exposure is assessed using the CCK-8 assay, while migration and invasion are evaluated through wound healing and Transwell assays. The effects of CHRNA5 knockdown and overexpression are also investigated. Immunofluorescence staining is used to analyze CHRNA5 expression and localization, and clonogenic assays are performed to measure colony proliferation after CHRNA5 knockdown and overexpression. The interaction between CHRNA5 and CES1 is examined using molecular docking, co-immunoprecipitation, and immunofluorescence. Differentially expressed genes are subjected to pathway enrichment analysis, and MEK/ERK protein expression and phosphorylation are validated via western blot. Tumor formation assays are performed in nude mice using sh-CHRNA5 Cal27 cells, followed by western blot and immunohistochemical staining. Additionally, laryngeal and hypopharyngeal cancer tissues are analyzed through immunohistochemistry. Nicotine significantly enhanced the proliferation, migration, and invasion capabilities of head and neck tumor cells, including Cal27, Fadu, HN6, and Tu686 cells, through the expression of CHRNA5. Knockdown of CHRNA5 can reduce cell migration, invasion, and proliferation, whereas nicotine exposure can reverse this trend. Additionally, the mRNA and protein expression of CES1 decreases with the knockdown of CHRNA5, indicating a regulatory relationship between the two. Transcriptomics revealed that the knockdown of CHRNA5 is associated with the MEK/ERK signaling pathway. Further cellular- and tissue-level evidence confirmed that the levels of p-MEK/MEK, p-ERK/ERK, and CES1 decreased following knockdown of CHRNA5, a trend that nicotine can reverse. Nicotine promotes the proliferation, migration, and invasion of HNSC by upregulating CHRNA5 expression. Knockdown of CHRNA5 reduces these effects, which can be reversed by nicotine. Nicotine exposure activates CHRNA5, regulating CES1 expression via the MEK/ERK pathway, contributing to the recurrence and metastasis of head and neck squamous carcinoma.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"785"},"PeriodicalIF":8.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544029","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}

{"title":"Ror2 signaling regulated by differential Wnt proteins determines pathological fate of muscle mesenchymal progenitors.","authors":"Koki Kamizaki, Mitsuko Katsukawa, Ayano Yamamoto, So-Ichiro Fukada, Akiyoshi Uezumi, Mitsuharu Endo, Yasuhiro Minami","doi":"10.1038/s41419-024-07173-9","DOIUrl":"10.1038/s41419-024-07173-9","url":null,"abstract":"<p><p>Skeletal muscle mesenchymal progenitors (MPs) play a critical role in supporting muscle regeneration. However, under pathological conditions, they contribute to intramuscular adipose tissue accumulation, involved in muscle diseases, including muscular dystrophy and sarcopenia, age-related muscular atrophy. How MP fate is determined in these different contexts remains unelucidated. Here, we report that Ror2, a non-canonical Wnt signaling receptor, is selectively expressed in MPs and regulates their pathological features in a differential ligand-dependent manner. We identified Wnt11 and Wnt5b as ligands of Ror2. In vitro, Wnt11 inhibited MP senescence, which is required for normal muscle regeneration, and Wnt5b promoted MP proliferation. We further found that both Wnts are abundant in degenerating muscle and synergistically stimulate Ror2, leading to unwanted MP proliferation and eventually intramuscular adipose tissue accumulation. These findings provide evidence that Ror2-mediated signaling elicited by differential Wnts plays a critical role in determining the pathological fate of MPs.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"784"},"PeriodicalIF":8.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521143","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}

{"title":"Correction to: Melatonin attenuates detrimental effects of diabetes on the niche of mouse spermatogonial stem cells by maintaining Leydig cells.","authors":"Zhaoyu Du, Shuanshuan Xu, Shuxian Hu, Hong Yang, Zhe Zhou, Kuldip Sidhu, Yiliang Miao, Zhonghua Liu, Wei Shen, Russel J Reiter, Jinlian Hua, Sha Peng","doi":"10.1038/s41419-024-07161-z","DOIUrl":"10.1038/s41419-024-07161-z","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"781"},"PeriodicalIF":8.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521134","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}

{"title":"Proteomic profiling reveals CEACAM6 function in driving gallbladder cancer aggressiveness through integrin receptor, PRKCD and AKT/ERK signaling.","authors":"Raisatun Nisa Sugiyanto, Carmen Metzger, Aslihan Inal, Felicia Truckenmueller, Kira Gür, Eva Eiteneuer, Thorben Huth, Angelika Fraas, Ivonne Heinze, Joanna Kirkpatrick, Carsten Sticht, Thomas Albrecht, Benjamin Goeppert, Tanja Poth, Stefan Pusch, Arianeb Mehrabi, Peter Schirmacher, Junfang Ji, Alessandro Ori, Stephanie Roessler","doi":"10.1038/s41419-024-07171-x","DOIUrl":"10.1038/s41419-024-07171-x","url":null,"abstract":"<p><p>Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the significantly most upregulated proteins in GBC. CEACAM6 overexpression has been observed in other cancer entities but the molecular function remains unclear. Our functional analyses in vitro and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression and metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation, and colony formation. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration. ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"780"},"PeriodicalIF":8.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521135","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}

{"title":"The link between amyloid β and ferroptosis pathway in Alzheimer's disease progression.","authors":"Naďa Majerníková, Alejandro Marmolejo-Garza, Casandra Salinas Salinas, Minh D A Luu, Yuequ Zhang, Marina Trombetta-Lima, Tamara Tomin, Ruth Birner-Gruenberger, Šárka Lehtonen, Jari Koistinaho, Justina C Wolters, Scott Ayton, Wilfred F A den Dunnen, Amalia M Dolga","doi":"10.1038/s41419-024-07152-0","DOIUrl":"10.1038/s41419-024-07152-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease's impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"782"},"PeriodicalIF":8.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521144","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}