Oxidative stress-induced astrocytic collagen biosynthesis drives glial barrier formation and neuronal death in ischemic stroke.

Abstract

Astrocytes regulate brain metabolism and homeostasis, but how oxidative stress reshapes astrocytic metabolism to drive neuronal damage remains unclear. Here, we demonstrate that oxidative stress turns on astrocytic type I collagen (COL1) production via a redox-glycosylation coupling mechanism. Hydrogen peroxide (H₂O₂) suppresses miR-29 and enhances fucosyltransferase 8 (FUT8)-mediated core fucosylation, integrating post-transcriptional and glycosylation-dependent regulation of COL1. Astrocyte-derived COL1 activates integrin signaling and promotes neuronal death. In a photothrombotic stroke model, an H₂O₂ surge induces astrogliosis, glycosylation remodeling, and COL1 expression, leading to glial barrier formation, neuronal loss, and neurological deficits. These pathological cascades are mitigated by astrocyte-specific silencing of COL1 or FUT8 or by KDS12025, a peroxidase enhancer that reduces H₂O₂ burden. Notably, KDS12025 exerts potent neuroprotection in a non-human primate stroke model. Together, our findings identify an unprecedented astrocytic metabolic pathway linking oxidative stress to glycosylation-driven COL1 production, highlighting the H₂O₂ surge, astrocytic COL1, and FUT8 as promising therapeutic targets for recovery after stroke.