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Effective treatment strategies for ischemic conditions require extensive knowledge of the signaling pathways and mechanisms underlying ischemic pathophysiology. This study aims to uncover the neuroprotective role of ND2 in ischemia and its interactions with critical signaling pathways implicated in recovery. An in vitro ischemic stroke model oxygen\u2013glucose deprivation (OGD) method was applied to neuro-2A (N2a) cells with lentiviral ND2 (LvND2) overexpression. DNA fragmentation and cell survival assays indicated ND2\u2019s neuroprotective and anti-apoptotic effects under OGD conditions. Proteomic profiling and interaction analyses showed that LvND2 regulated the synthesis of cellular signaling, proliferation and cell adhesion-related proteins, such as MAPK3, Mki67, and NCAM. Additionally, a positive correlation was observed between ND2 expression and phosphorylated AKT levels. To investigate the interaction between ND2 and the PI3K\/AKT signaling pathway, the pathway was pharmacologically inhibited with Wortmannin 30\u00a0min before OGD induction. After 8\u00a0h of OGD followed by 16\u00a0h of reperfusion, cell survival, DNA fragmentation, and Western blot analyses were performed. LvND2 administration alone increased cellular survival, whereas its combination with Wortmannin resulted in decreased cell survival. Additionally, LvND2 alone reduced the number of TUNEL-positive cells, while its combination with Wortmannin remains non-significant. These findings suggest that ND2 and AKT function in a coordinated manner within the PI3K\/AKT survival pathway. ND2 may modulate AKT activity, highlighting its potential as a therapeutic target for addressing ischemic pathophysiology through molecular therapies.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s12017-025-08852-2","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T10:37:58Z","timestamp":1744799878000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unraveling the Role of NeuroD2 in Ischemic Pathophysiology: Insight into Neuroprotection Mechanisms Associated with AKT Survival Kinase"],"prefix":"10.1007","volume":"27","author":[{"given":"Busenur","family":"Bolat","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cigdem","family":"Bayraktaroglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zehra","family":"Degirmenci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ecem","family":"Cerah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehmet","family":"Sali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edanur","family":"Kolcu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dila Nur","family":"Bars","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cemil","family":"Aydin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Abasova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulla","family":"Alisoy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hasan Ege","family":"Atali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mustafa Caglar","family":"Beker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulkan","family":"Celik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merve","family":"Beker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"issue":"4","key":"8852_CR1","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1007\/s12035-022-02745-2","volume":"59","author":"M Babu","year":"2022","unstructured":"Babu, M., Singh, N., & Datta, A. 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