# Puerarin Attenuates White Matter Injury and Blood–Brain Barrier Disruption After Intracerebral Hemorrhagic Stroke via cGAS-STING Axis

## TL;DR

Puerarin helps reduce brain damage after a type of stroke by targeting a specific pathway, offering a potential new treatment.

## Contribution

Puerarin's novel role in modulating the cGAS-STING pathway to protect the brain after stroke is first demonstrated.

## Key findings

- Puerarin improved neurological outcomes and reduced BBB permeability in ICH mice.
- Puerarin suppressed cGAS-STING activation, reducing oligodendrocyte apoptosis and promoting remyelination.
- Twenty-six hub genes were identified, linked to cGAS-STING and AKT1-mTOR pathways.

## Abstract

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke, often leading to severe white matter injury (WMI) and blood–brain barrier (BBB) disruption, which culminate in devastating neurological deficits. Currently, no effective pharmacological treatments exist. In this study, we investigated the protective effects of puerarin on WMI and BBB integrity in ICH. Using a combination of network pharmacology, transcriptomic analysis, and machine learning, we identified key genes associated with WMI in ICH. Molecular docking and molecular dynamics simulations were then employed to evaluate the stability of puerarin potential binding to these target proteins. Importantly, our study demonstrates for the first time that puerarin can modulate the cGAS-STING signaling pathway in a mouse model of ICH, thereby alleviating white matter damage and BBB disruption.

White matter injury (WMI) and blood–brain barrier (BBB) disruption contribute to neurological and cognitive deficits in intracerebral hemorrhage (ICH), with no effective pharmacological treatments available. Puerarin, with anti-inflammatory, anti-apoptotic, and antioxidant properties, exhibits neuroprotective potential. Here, mice subjected to ICH were treated with puerarin for 14 days. Neurological function, cerebral perfusion, and BBB integrity were assessed using behavioral tests, laser speckle imaging, Evans blue assays, immunofluorescence, Western blotting, and MRI. Integrated transcriptomics, machine learning, network pharmacology, molecular docking, and dynamics simulations were used to identify key targets. Puerarin improved neurological outcomes, reduced BBB permeability, enhanced microvascular perfusion, and attenuated WMI. Twenty-six hub genes were identified, with PARP1 and AKT1 correlated with OLIG2 and MBP, enriched in the cGAS-STING and AKT1-mTOR pathways. Molecular simulations indicated stable puerarin–cGAS interactions, validated experimentally: puerarin suppressed cGAS-STING activation, reduced oligodendrocyte apoptosis, and promoted remyelination. These results provide new insights into ICH pathogenesis and support puerarin as a potential therapeutic agent for BBB disruption and WMI.