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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\u2013cGAS 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.<\/jats:p>","DOI":"10.3390\/biology15030277","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T12:46:11Z","timestamp":1770122771000},"page":"277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Puerarin Attenuates White Matter Injury and Blood\u2013Brain Barrier Disruption After Intracerebral Hemorrhagic Stroke via cGAS-STING Axis"],"prefix":"10.3390","volume":"15","author":[{"given":"Yetong","family":"Ouyang","sequence":"first","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijia","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Shi","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"},{"name":"Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilin","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Tang","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Jin","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhexue","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshun","family":"Tang","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"},{"name":"Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijin","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Translational Neurodegeneration and Regenerative Therapy, School of Medicine, Tongji University, Shanghai 200333, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2942","DOI":"10.1161\/STROKEAHA.124.048533","article-title":"Intracerebral Hemorrhage: Keep It Simple","volume":"55","author":"Hanley","year":"2024","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1177\/0271678X251314366","article-title":"Circulating molecules reflect imaging biomarkers of hemorrhage in cerebral cavernous malformations","volume":"45","author":"Hage","year":"2025","journal-title":"J. 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