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A CRISPR-Cas9 loss-of-function screen identified key ferroptosis regulators and demonstrated a TRIM25–VDAC2 axis that suppresses ferroptosis, while an Angiopep-2-modified delivery system promotes ferroptosis and inhibits tumor growth.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/targeting-trim25-as-a-therapeutic-strategy-to-enhance-ferroptosis-in-glioblastoma-cells/457649/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/targeting-trim25-as-a-therapeutic-strategy-to-enhance-ferroptosis-in-glioblastoma-cells/457649.png","ImageObject",300,407,{"name":92,"@type":93},"pop out","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-08","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does ferroptosis play in glioblastoma, according to the study?","Question",{"text":112,"@type":113},"Ferroptosis is described as the most enriched programmed cell death process and is highly correlated with GBM malignant progression.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the researchers identify key contributors to ferroptosis?",{"text":117,"@type":113},"They used a CRISPR-Cas9 loss-of-function screen to find critical ferroptosis contributors, followed by mechanistic analyses of mitochondrial function and relevant protein pathways.",{"name":119,"@type":110,"acceptedAnswer":120},"What therapeutic strategy targets TRIM25, and what was its effect in vivo?",{"text":121,"@type":113},"TRIM25 targeting was delivered using Angiopep-2-modified nanoparticles carrying Cas9/sgRNA (ANPSS, sgTRIM25). 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Journal of Nanobiotechnology (2026) 24:20  \n[https://doi.org/10.1186/s12951-025-03908-8](https://doi.org/10.1186/s12951-025-03908-8)  \nJournal of Nanobiotechnology  \nRESEARCH Open Access  \nTargeting TRIM25 as a therapeutic strategy to enhance ferroptosis in glioblastoma cells  \nMaorong Zhu1†, Yuxin Wu1†, Huihui Ou1†, Xiao Liu1,2, Yawen Wang3, Xiaolin Liu4, Cheng Zou1, Guangzhao Yang2, Mingrui Du5, Duo Yu6, Dan Zheng1, Lei He1, Kuo Zhang1, Wangqian Zhang1, Shuning Wang1, Haozhe Qin2, Qiang Hao1, Yalong He2, Wei Lin2,7, Yingqi Zhang1, Jintao Gu1*, Meng Li1*, Weidong Qin8* and Zhengcong Cao1*  \nAbstract  \nBackground Glioblastoma (GBM) is the most common malignant brain tumor with a dismal prognosis (\u003C 7% 5-year survival) under current first-line treatment. While inducing programmed cell death (PCD) is a promising antitumor strategy, its effectiveness in GBM remains controversial. Ferroptosis emerged as the most enriched PCD process and was highly correlated with GBM malignant progression.  \nMethods We performed a CRISPR-Cas9 loss-of-function screen to identify critical ferroptosis contributors. Mechanistic studies involved assessing mitochondrial function and morphology. Protein interaction and degradation pathways were investigated using immunoprecipitation and ubiquitination assays. We developed a blood-brainbarrier-penetrating genome editing delivery system, Angiopep-2-modified nanoparticles with disulfide bonds (ANPSS), loaded with Cas9/sgRNA complexes.  \nResults Voltage-dependent anion channel 2 (VDAC2) was identified as a critical contributor to ferroptosis. VDAC2 overexpression induced mitochondrial dysfunction and characteristic ferroptotic mitochondrial morphology. The E3 ubiquitin ligaseTRIM25 was identified as a key suppressor of VDAC2, directly interacting with it and inducing its K48-linked polyubiquitination and subsequent proteasomal degradation. In vivo, the ANPSS(sgTRIM25) system effectively targeted GBM cells, significantly promoted ferroptosis, and inhibited GBM progression.  \nConclusions Our findings demonstrate that TRIM25 is a critical negative regulator of VDAC2-dependent ferroptosisin GBM. Targeting TRIM25 using the ANPSS(sgTRIM25) genome editing system effectively overcomes ferroptosis resistance and suppresses tumor growth, representing a viable therapeutic approach for GBM.  \nKeywords CRISPR screens, Glioblastoma, TRIM25, VDAC2, Gene editing, Ferroptosis  \n†Maorong Zhu, Yuxin Wu and Huihui Ou contributed equally to this work.  \n*Correspondence:  \nJintao Gu[gujintao@fmmu.edu.cn](gujintao@fmmu.edu.cn)[ ](gujintao@fmmu.edu.cn)Meng Li  \n[limeng@fmmu.edu.cn](limeng@fmmu.edu.cn)[ ](limeng@fmmu.edu.cn)Weidong Qin [qinweidong@fmmu.edu.cn](qinweidong@fmmu.edu.cn)[ ](qinweidong@fmmu.edu.cn)Zhengcong Cao [caozhengcong0928@163.com](caozhengcong0928@163.com)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd","cbCaihSk8bLGPUyV","https://ap.wps.com/l/cbCaihSk8bLGPUyV","pdf",6159819,"English","# Abstract\n# Background\n# Methods\n# Results\n# Conclusions\n# Keywords","[{\"question\":\"What role does ferroptosis play in glioblastoma, according to the study?\",\"answer\":\"Ferroptosis is described as the most enriched programmed cell death process and is highly correlated with GBM malignant progression.\"},{\"question\":\"How did the researchers identify key contributors to ferroptosis?\",\"answer\":\"They used a CRISPR-Cas9 loss-of-function screen to find critical ferroptosis contributors, followed by mechanistic analyses of mitochondrial function and relevant protein pathways.\"},{\"question\":\"What therapeutic strategy targets TRIM25, and what was its effect in vivo?\",\"answer\":\"TRIM25 targeting was delivered using Angiopep-2-modified nanoparticles carrying Cas9/sgRNA (ANPSS, sgTRIM25). The system targeted GBM cells, promoted ferroptosis, and inhibited GBM progression.\"}]","Targeting TRIM25 as a therapeutic strategy to enhance ferroptosis in glioblastoma cells | PDF",1790750074,48]