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Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has been implicated in the pathophysiology of mTBI. However, its precise role in mTBI - induced cognitive dysfunction and potential therapeutic strategies remain unclear. This study aimed to investigate the neuroprotective effects of mesenchymal stem cell - derived exosomes (MSC - Exos) against ferroptosis and cognitive dysfunction following mTBI. We established an mTBI rat model and administered MSC - Exos at different doses. Behavioral assessments, histological and molecular biological analyses, and bioinformatics approaches were used. The results showed that mTBI rats exhibited cognitive impairments, increased lipid peroxidation, and reduced GPX4 expression. MSC - Exos treatment improved cognitive function in a dose - dependent manner, attenuated lipid peroxidation, and restored GPX4 expression. Transcriptomic and bioinformatic analyses revealed that MSC - Exos activated the PI3K\/AKT\/mTOR signaling pathway, which upregulated GPX4 expression and inhibited ferroptosis. In conclusion, MSC - Exos alleviate cognitive deficits after mTBI by inhibiting ferroptosis via PI3K\/AKT\/mTOR - mediated upregulation of GPX4, providing a novel therapeutic strategy for mTBI.<\/jats:p>","DOI":"10.1007\/s10142-025-01760-5","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T01:11:31Z","timestamp":1763601091000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["MSC-Exosomes alleviate cognitive impairment after mild traumatic brain injury by inhibiting ferroptosis via PI3K\/AKT\/mTOR-mediated upregulation of GPX4"],"prefix":"10.1007","volume":"25","author":[{"given":"Haoyang","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengfa","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"issue":"12","key":"1760_CR1","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1001\/jamasurg.2024.4285","volume":"159","author":"AK Malhotra","year":"2024","unstructured":"Malhotra AK, Jaffe RH, Shakil H, Mathieu F, Nathens AB, Kulkarni AV, Diep C, Yuan EY, Ladha KS, Coyte PC, Wilson JR, Wodchis WP, Witiw CD (2024) Unemployment and personal income loss after traumatic brain injury. 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