USP11‐PGAM5 Axis Promotes Neurotoxic Astrocyte Reactivity by Aggravating the mtDNA‐cGAS‐STING Pathway After Intracerebral Hemorrhage

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.