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Despite their different primary insults, both conditions trigger a complex cascade of secondary brain injury that largely determines neurological outcome. This review systematically compares the epidemiology, shared molecular pathways, and emerging therapeutic strategies for secondary brain injury after ischemic stroke and traumatic brain injury. We focus on three interconnected pathological cascades spanning blood\u2013brain barrier disruption, neuroinflammation, and neuronal death driven by excitotoxicity, oxidative stress, and multiple forms of programmed cell death. For each pathway, we highlight convergent and divergent mechanisms between the two disorders. We then summarize emerging preclinical interventions ranging from small molecule inhibitors and repurposed drugs to nanomedicine, extracellular vesicles, and neuromodulation techniques. In parallel, we review recent and ongoing clinical trials targeting these pathways, emphasizing mechanism\u2010based strategies. Finally, we discuss current challenges and offer future perspectives on biomarker\u2010driven patient stratification, innovative drug delivery systems bypassing the blood\u2013brain barrier, and multitarget combination regimens. By providing a unified framework that compares ischemic stroke and traumatic brain injury side by side, this review aims to guide the development of more effective, personalized treatments for secondary brain injury.<\/jats:p>","DOI":"10.1002\/mco2.71053","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T08:04:27Z","timestamp":1791533067000},"source":"Crossref","is-referenced-by-count":0,"title":["Ischemic Stroke and Traumatic Brain Injury: Epidemiology, Molecular Pathways, and Emerging Therapies"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0933-1899","authenticated-orcid":false,"given":"Mengzhao","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Zhengzhou University  Zhengzhou City Henan Province China"},{"name":"State Key Laboratory of Biomedical Imaging Science and System Institute of Biomedicine and Biotechnology Shenzhen Institute of 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