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Cell. Neurosci."],"abstract":"<jats:p>Ischemic stroke remains a leading cause of death and long-term disability, yet effective treatments that promote recovery beyond the acute phase are lacking. Neuregulin-1 (NRG-1) has shown potent neuroprotective and anti-inflammatory properties in preclinical stroke models, with evidence of enhanced neuronal regeneration when administered after injury. To investigate the spatial mechanisms underlying its neuroregenerative therapeutic effects, we examined brain proteomic responses to post-ischemic NRG-1 treatment in mice using NanoString Digital Spatial Profiling (DSP). Adult C57BL\/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and treated with NRG-1\u03b2 (5 \u03bcg\/kg\/day) or vehicle at 24- and 48-h post-stroke. Brains were collected at 3 days post-ischemia for spatial proteomic analysis of 68 neural proteins across the ischemic core, peri-infarct tissue, and peri-infarct normal tissue (PiNT). While NRG-1 did not significantly alter overall neuronal death, it markedly reshaped the neuroregenerative milieu, upregulating myelin basic protein (MBP) and synaptophysin and attenuating inflammatory mediators (SPP1, P2RX7, and CD39). NRG-1 also enhanced expression of autophagy and mitophagy markers (ULK1, LC3B, ATG5, PINK1, and Park7), suggesting restoration of cellular clearance and mitochondrial quality control. Pathway and network analyses revealed activation of neuroregeneration, autophagy, and lysosomal biogenesis pathways, while suppressing neuroinflammatory signaling. These findings demonstrate that delayed NRG-1 therapy, even when initiated 24 h after stroke, induces early molecular programs that prime an anti-inflammatory and neuroregenerative environment. The results support further development of NRG-1 as a clinically translatable, multimodal therapy for extending the post-stroke treatment window and promoting functional recovery.<\/jats:p>","DOI":"10.3389\/fncel.2026.1739619","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T04:29:32Z","timestamp":1780374572000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Neuregulin-1 promotes early regenerative and autophagic responses after ischemic stroke via spatial proteomics"],"prefix":"10.3389","volume":"20","author":[{"given":"Jessica M.","family":"Noll","sequence":"first","affiliation":[{"name":"Division of Biomedical Sciences, University of California-Riverside School of Medicine","place":["Riverside, CA, United States"]},{"name":"Department of Statistics, University of California","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"McGinley","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Howard University College of Medicine","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J.","family":"Augello","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, University of California-Riverside School of Medicine","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esra","family":"K\u00fcr\u00fcm","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of California","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuliu","family":"Pan","sequence":"additional","affiliation":[{"name":"Nanostring Technologies","place":["Seattle, WA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pavenko","sequence":"additional","affiliation":[{"name":"Nanostring Technologies","place":["Seattle, WA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Nam","sequence":"additional","affiliation":[{"name":"Nanostring Technologies","place":["Seattle, WA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron D.","family":"Ford","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, University of California-Riverside School of Medicine","place":["Riverside, CA, United States"]},{"name":"Department of Anatomy, Howard University College of Medicine","place":["Washington, DC, United States"]},{"name":"Department of Bioengineering, University of California, Riverside","place":["Riverside, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Howard University College of Medicine","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.4161\/auto.3412","article-title":"The roles of autophagy in cerebral ischemia","volume":"3","author":"Adhami","year":"2007","journal-title":"Autophagy"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/glia.23150","article-title":"Neuregulin-1 positively modulates glial response and improves neurological recovery following traumatic spinal cord injury","volume":"65","author":"Alizadeh","year":"2017","journal-title":"Glia"},{"key":"B3","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1097\/00004647-199908000-00001","article-title":"Inflammatory mediators and stroke: new opportunities for novel therapeutics","volume":"19","author":"Barone","year":"1999","journal-title":"J. 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