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

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