ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
USP11-PGAM5 Axis Promotes Neurotoxic Astrocyte Reactivity by Aggravating the mtDNA-cGAS-STING Pathway After Intracerebral Hemorrhage.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Graded traumatic brain injury severity differentially modulates microglial and astrocytic polarization states and response to minocycline.Neuroprotection (Chichester, England) · 2026Article
- Environmental enrichment mitigates sevoflurane-induced neurodevelopmental injury via cGAS-STING-dependent microglial modulation.Cell & bioscience · 2026Article
- Expanding roles of cGAS-STING signaling in neuroinflammation.The Journal of clinical investigation · 2026Review
- Semaglutide targets the Isg15-FUNDC1 axis: suppressing IFN-β overactivation and attenuating blood-brain barrier injury in diabetic intracerebral hemorrhage.Journal of neuroinflammation · 2026Article
- Inhibition of Astrocytic JMJD3 Attenuates Neuroinflammation-Mediated Blood-Brain Barrier Disruption and Improves Functional Recovery After Intracerebral Hemorrhage in Mice.Brain sciences · 2026Article
- Bioengineering of extracellular vesicles with scaffold proteins for drug delivery.Journal of nanobiotechnology · 2026Review
- USP11-PGAM5 Axis Promotes Neurotoxic Astrocyte Reactivity by Aggravating the mtDNA-cGAS-STING Pathway After Intracerebral Hemorrhage.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mitochondrial dysfunction in intracerebral hemorrhage: molecular mechanisms and pathological consequences.Frontiers in cellular neuroscience · 2026Review
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
Astrocyte 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 phosphoglycerate mutase family member 5 (PGAM5). Furthermore, USP11 is identified as a novel deubiquitinase of PGAM5, 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 mtDNA-cGAS-STING pathway after ICH.
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Registered trials
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