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Neurosci."],"accepted":{"date-parts":[[2025,8,3]]},"published-print":{"date-parts":[[2025,9,17]]},"abstract":"<jats:p>\n<jats:italic>MiRNA<\/jats:italic>\n-based therapeutics represent a promising approach for treating multiple diseases, yet the key regulatory\n<jats:italic>miRNAs<\/jats:italic>\nin chronic cerebral hypoperfusion (CCH)-related cognitive impairment remains unclear. Here, we identify\n<jats:italic>miR-153<\/jats:italic>\nas consistently upregulated in both male and female mild cognitive impairment (MCI) and late-stage of Alzheimer's disease (AD) patients, as well as in the basal forebrain of both male and female postmortem AD specimens and male CCH rats. Knockdown of\n<jats:italic>miR-153<\/jats:italic>\nin the basal forebrain alleviated CCH-induced cognitive deficits. Mechanistically,\n<jats:italic>miR-153<\/jats:italic>\ndirectly targeted Karyopherin alpha 5 (KPNA5), a nuclear transport protein that facilitates nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation.\n<jats:italic>miR-153<\/jats:italic>\nsuppressed\n<jats:italic>KPNA5<\/jats:italic>\nvia two binding sites in its 3'UTR, impairing NRF2-mediated antioxidant responses and promoting oxidative stress, and KPNA5 bound to three nuclear localization sequences of NRF2 through protein interaction. Restoration of the\n<jats:italic>miR-153<\/jats:italic>\n-KPNA5-NRF2 axis in the basal forebrain alleviated oxidative stress damage in male CCH rats, while no such effect was observed in the hippocampus. These findings reveal a potential role of the\n<jats:italic>miR-153<\/jats:italic>\n-KPNA5-NRF2 axis in CCH-related cognitive decline.\n<\/jats:p>","DOI":"10.1523\/jneurosci.2148-24.2025","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T19:00:10Z","timestamp":1755284410000},"page":"e2148242025","update-policy":"https:\/\/doi.org\/10.1523\/jneurosci.crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["<i>MiR-153<\/i>\nPrevents NRF2 Nuclear Translocation to Drive Hypoperfusion-Related Cognitive Deficits by Targeting\n<i>KPNA5<\/i>"],"prefix":"10.1523","volume":"45","author":[{"given":"Yang","family":"Qu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guitian","family":"Cong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fucong","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyou","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"2025091711001528000_45.38.e2148242025.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M709572200"},{"key":"2025091711001528000_45.38.e2148242025.2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05005"},{"key":"2025091711001528000_45.38.e2148242025.3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1997-12.2013"},{"key":"2025091711001528000_45.38.e2148242025.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.09.006"},{"key":"2025091711001528000_45.38.e2148242025.5","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13163"},{"key":"2025091711001528000_45.38.e2148242025.6","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bby054"},{"key":"2025091711001528000_45.38.e2148242025.7","doi-asserted-by":"crossref","first-page":"e2850","DOI":"10.1038\/cddis.2017.243","article-title":"MicroRNA-195 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