<i>MiR-153</i>Prevents NRF2 Nuclear Translocation to Drive Hypoperfusion-Related Cognitive Deficits by Targeting<i>KPNA5</i>

<i>MiRNA</i>-based therapeutics represent a promising approach for treating multiple diseases, yet the key regulatory <i>miRNAs</i> in chronic cerebral hypoperfusion (CCH)-related cognitive impairment remains unclear. Here, we identify <i>miR-153</i> as 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 <i>miR-153</i> in the basal forebrain alleviated CCH-induced cognitive deficits. Mechanistically, <i>miR-153</i> directly targeted Karyopherin alpha 5 (KPNA5), a nuclear transport protein that facilitates nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation. <i>miR-153</i> suppressed <i>KPNA5</i> via 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 <i>miR-153</i>-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 <i>miR-153</i>-KPNA5-NRF2 axis in CCH-related cognitive decline.