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

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 <i>PARP1</i> and <i>AKT1</i> correlated with <i>OLIG2</i> and <i>MBP</i>, 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.