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Analyses of perihematomal tissue from ICH patients and mice show neurotoxic astrocyte reactivity correlates with PGAM5 expression. USP11 is identified as a deubiquitinase of PGAM5 that elevates PGAM5 by suppressing ubiquitin-proteasome degradation. Astrocyte-specific Usp11 or Pgam5 knockout reduces neurotoxic reactivity, neuronal apoptosis, and supports neurofunctional recovery via mtDNA leakage and cGAS-STING activation, and engineered vesicles delivering Pgam5 siRNA improve outcomes.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/usp11-pgam5-axis-promotes-neurotoxic-astrocyte-reactivity-by-aggravating-the-mtdna-cgas-sting-pathway-after-intracerebral-hemorrhage/439691/",{"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/usp11-pgam5-axis-promotes-neurotoxic-astrocyte-reactivity-by-aggravating-the-mtdna-cgas-sting-pathway-after-intracerebral-hemorrhage/439691.png","ImageObject",300,407,{"name":92,"@type":93},"Rizky","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-02","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What links USP11-PGAM5 signaling to neurotoxic astrocyte reactivity after ICH?","Question",{"text":112,"@type":113},"USP11 acts as a deubiquitinase for PGAM5, suppressing its ubiquitin-proteasome degradation and increasing PGAM5 levels. Elevated PGAM5 promotes mitochondrial dysfunction that drives mtDNA leakage and cGAS-STING pathway activation, amplifying neurotoxic astrocyte reactivity.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do PGAM5 and mitochondrial pathways contribute mechanistically?",{"text":117,"@type":113},"PGAM5 promotes mitochondrial permeability transition pore (mPTP) opening and Drp1-mediated mitochondrial fission. These changes synergistically amplify mitochondrial DNA leakage, triggering cGAS-STING signaling.",{"name":119,"@type":110,"acceptedAnswer":120},"Can blocking mtDNA or cGAS-STING reduce the neurotoxic phenotype?",{"text":121,"@type":113},"Yes. Clearing mtDNA or blocking the cGAS-STING pathway attenuates USP11-PGAM5-driven neurotoxic astrocyte reactivity, indicating the pathway’s causal role.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},439691,1790707178,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31},962085564807,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nUSP11-PGAM5 Axis Promotes Neurotoxic Astrocyte Reactivity by Aggravating the mtDNA-cGAS-STING Pathway After Intracerebral Hemorrhage  \nJiaqing He, Zijuan Qin, Yaning Cai, Haixiao Liu, Tinghao Wang, Qing Hu, Yanni Xu, Pan Yang, Xun Wu,* Yan Qu,* and Wei Guo*  \nAstrocyte transformation into a neurotoxic phenotype is a hallmark pathological feature of intracerebral hemorrhage (ICH) and a key contributor to exacerbating secondary brain injury. Understanding the underlying mechanisms that regulate the reactivity of neurotoxic astrocytes is critical for developing targeted treatment strategies for ICH. In this study, analyses of perihematomal tissue from ICH patients and mice reveal that neurotoxic astrocyte reactivity correlates with expression levels of phosphoglyceratemutase family member 5 (PGAM5). Furthermore, USP11 is identified as a novel deubiquitinase ofPGAM5, which contributes to elevated PGAM5 expression in neurotoxic astrocytes by suppressing its ubiquitin-proteasome degradation. Astrocyte-specific Usp11 or Pgam5 knockout suppresses neurotoxic astrocyte reactivity, reduces neuronal apoptosis, and facilitates neurofunctional recovery. Mechanistically, PGAM5 promotes mitochondrial permeability transition pore (mPTP) opening and dynamin-related protein 1 (Drp1) mediated mitochondrial fission, synergistically amplifying mitochondrial DNA (mtDNA) leakage, and cGAS-STING pathway activation. Clearing mtDNA or blocking cGAS-STING pathway effectively attenuates USP11-PGAM5-driven neurotoxic astrocyte reactivity. Furthermore, extracellular vesicles modified by angiopep-2 are engineered for blood-brain barrier-penetrating delivery of Pgam5-targeting small interfering RNA, which significantly improves neurological function after ICH. In summary, the findings unveil an unrecognized mechanistic role for the USP11-PGAM5 axis in driving neurotoxic astrocyte reactivity by regulating the  \nmtDNA-cGAS-STING pathway after ICH.  \n1. Introduction  \nIntracerebral hemorrhage (ICH) is a lifethreatening form of acute brain injury, resulting in ≈2.8 million deaths worldwide annually.[1] Due to the irreversible neurological damage and inadequate treatment options, survivors of ICH often suffer from neurological function deficits. Astrocytes, the most abundant resident cells in the central nervous system (CNS), play a crucial role in maintaining CNS homeostasis and performing various complex functions. [2] In response to ICH injury, astrocytes undergo a process known as “reactive astrocytosis,” which has emerged as a pathological hallmark of ICH. [3,4] Recent studies have revealed that reactive astrocytes exhibit marked heterogeneity and can exert both detrimental and neuroprotective effects within the CNS. [5,6] Among these, neurotoxic astrocytes have been reported to be induced by inflammatory microglia through their secretion of IL-1􀀂, TNF-􀀂, and C1q.[7,8] This phenotype is characterized by the loss of essential astrocytic functions and increased release of neurotoxins. [7] Furthermore, such astrocytes can exacerbate brain injury by remodeling the cerebral immune microenvironment via secretion of  \nJ. He  \nDepartment of Neurosurgery Xi’an Medical University Xi’an, Shaanxi 710021, China  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202514283](https://doi.org/10.1002/advs.202514283)[ ](https://doi.org/10.1002/advs.202514283)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202514283  \nJ. He, Y. Cai, H. Liu, T. Wang, P. Yang, X. Wu, Y. Qu, W. Guo Department of Neurosurgery  \nTangdu Hospital  \nthe Fourth Military Medical University  \nXi’an, Shaanxi 710032, China [E-mail:](E-mail: w","cbCaiusRIasZQKqe","https://ap.wps.com/l/cbCaiusRIasZQKqe","pdf",17742225,"English","# Introduction\n## Reactive astrocytosis and neurotoxic astrocytes in ICH\n## Mitochondrial damage, mtDNA leakage, and cGAS-STING\n## PGAM5 as a regulator of mitochondrial dynamics and cell death","[{\"question\":\"What links USP11-PGAM5 signaling to neurotoxic astrocyte reactivity after ICH?\",\"answer\":\"USP11 acts as a deubiquitinase for PGAM5, suppressing its ubiquitin-proteasome degradation and increasing PGAM5 levels. Elevated PGAM5 promotes mitochondrial dysfunction that drives mtDNA leakage and cGAS-STING pathway activation, amplifying neurotoxic astrocyte reactivity.\"},{\"question\":\"How do PGAM5 and mitochondrial pathways contribute mechanistically?\",\"answer\":\"PGAM5 promotes mitochondrial permeability transition pore (mPTP) opening and Drp1-mediated mitochondrial fission. These changes synergistically amplify mitochondrial DNA leakage, triggering cGAS-STING signaling.\"},{\"question\":\"Can blocking mtDNA or cGAS-STING reduce the neurotoxic phenotype?\",\"answer\":\"Yes. Clearing mtDNA or blocking the cGAS-STING pathway attenuates USP11-PGAM5-driven neurotoxic astrocyte reactivity, indicating the pathway’s causal role.\"}]","USP11-PGAM5 Axis Promotes Neurotoxic Astrocyte Reactivity by Aggravating the mtDNA-cGAS-STING Pathway After Intracerebral Hemorrhage | PDF",1790689910]