{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T16:13:28Z","timestamp":1754151208195,"version":"3.41.2"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec034\">\n<jats:title>Background<\/jats:title>\n<jats:p>Secondary brain injury following intracerebral hemorrhage (ICH) is a critical clinical challenge, yet the molecular mechanisms driving neuronal damage remain poorly understood. This study investigates the role of the transcription factor ATF3 and its downstream effector, VASP, in mediating neuronal injury via the platelet activation pathways.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec035\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Differential gene expression analysis of the GSE24265 dataset was conducted using the limma package in R to identify key regulators in hemorrhagic conditions. Protein\u2013protein interaction network analysis and bioinformatic predictions were employed to pinpoint central regulatory nodes and downstream targets. Validation experiments utilized the HT22 mouse hippocampal neuronal cell line, combining ATF3 overexpression\/knockdown, dual luciferase reporter assays, and functional assessments (propidium iodide\/Calcein-AM staining, flow cytometry). Enrichment analysis linked identified targets to biological pathways.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec036\">\n<jats:title>Results<\/jats:title>\n<jats:p>ATF3 was significantly upregulated in hemorrhagic conditions and identified as a central regulatory node. Bioinformatic and experimental validation confirmed VASP as a direct downstream target of ATF3. Enrichment analysis revealed VASP\u2019s predominant association with platelet activation pathways. Functional assays demonstrated that ATF3 overexpression exacerbated heme-induced cytotoxicity in HT22 cells, implicating hyperactive platelet activation in secondary neuronal damage.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec037\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>This study identifies a novel ATF3\u2013VASP signaling axis as a key driver of secondary neuronal injury post-ICH. Our findings advance the mechanistic understanding of post-hemorrhagic brain damage and suggest that therapeutic targeting of the ATF3\u2013VASP pathway may mitigate secondary injury, offering a potential strategy to improve clinical outcomes.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0328530","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T17:30:26Z","timestamp":1752859826000},"page":"e0328530","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated bioinformatics and experimental validation identify ATF3 as a key gene in secondary brain damage after intracerebral 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