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Oxidative stress and mitochondrial dysfunction play a critical role in the progression of DR. Mounting data indicated that small extracellular vesicles (sEVs) of mesenchymal stem cell (MSC) have the ability to transport bioactive chemicals to target cells, leading to changes in their phenotype. Nevertheless, it remains elusive how MSC-derived sEVs regulate oxidative stress and mitochondrial function in DR. MSC-sEVs was intravitreally injected to streptozotocin (STZ)-treated Sprague-Dawley rats to assess the therapeutic effects on DR. The underlying regulatory mechanism was investigated by coculturing advanced glycation end-products (AGEs)-induced rat M\u00fcller cells with\/without PTP1B overexpression with MSC-sEVs in vitro, with or without miR-125a-5p suppression. Intravitreal injection of MSC-sEVs improved histological morphology and blood-retinal barrier function, alleviated M\u00fcller gliosis, decreased PTP1B expression, redox stress and apoptosis in retina of diabetic rat. MSC-sEVs decreased the accumulation of ROS and improved the structure and function of mitochondria of M\u00fcller cells with AGEs treatment. Mechanically, MSC-sEVs activated the mitophagy of AGEs-treated M\u00fcller cells, represented by an increased expression of the LC3II\/LC3I ratio, TOM20, PINK1 and Parkin along with a decreased expression of P62. Importantly, miR-125a-5p inhibitor abolished the protective effects of MSC-sEVs. Furthermore, the overexpression of PTP1B in M\u00fcller cells reduced the effects of MSC-sEVs. These findings suggested that miR-125a-5p of MSC-sEVs alleviates M\u00fcller cells injury in DR by modulating PINK1\/Parkin-mediated mitophagy via PTP1B pathway.<\/jats:p>","DOI":"10.1038\/s41420-025-02439-3","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T08:38:44Z","timestamp":1746693524000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["MiR-125a-5p in MSC-derived small extracellular vesicles alleviates M\u00fcller cells injury in diabetic retinopathy by modulating mitophagy via PTP1B pathway"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2198-198X","authenticated-orcid":false,"given":"Cong","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3180-7012","authenticated-orcid":false,"given":"Jinjin","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8872-2910","authenticated-orcid":false,"given":"Yueqin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5125-3735","authenticated-orcid":false,"given":"Yinglin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huangyi","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genhong","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2587-157X","authenticated-orcid":false,"given":"Zhenggao","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"2439_CR1","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1136\/bjophthalmol-2013-304017","volume":"99","author":"RL Thomas","year":"2015","unstructured":"Thomas RL, Dunstan FD, Luzio SD, Chowdhury SR, North RV, Hale SL, et al. 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