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We employed transcriptomic analysis in an APP\/PSEN1 Tg AD mouse model to identify dysregulated miRNAs and construct a miRNA-mRNA-pathway network. We discovered increased miR7a expression in the AD brain, targeting Kr\u00fcppel-like factor 4 (Klf4), a transcriptional factor implicated in A\u03b2 oligomer-induced neuroinflammation and RSL3-induced neuronal ferroptosis. Elevated Klf4 levels in AD mice brains suggest its involvement in AD pathology. The miR-7a mediated silencing of Klf4 alleviates neuroinflammation by modulating NF-\u03baB, iNOS, and NLRP3 pathways, and inhibition of ferroptosis by targeting labile iron levels, GPX4, Nrf2 pathway, and mitochondrial damage. These findings highlight the neuroprotective role of miR-7a and its potential as RNA therapeutic. Pharmacological targeting of the miR-7a-Klf4 axis with blood-brain-barrier (BBB)-permeable compound effectively mitigates neuroinflammation and ferroptosis, suggesting the miR-7a-Klf4 axis as a novel therapeutic target for AD.<\/jats:p>\n                <jats:sec>\n                  <jats:title>GRAPHICAL ABSTRACT<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"644978v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.24.644978","type":"posted-content","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T02:29:57Z","timestamp":1742956197000},"source":"Crossref","is-referenced-by-count":4,"title":["MiR-7a-Klf4 axis as a regulator and therapeutic target of neuroinflammation and ferroptosis in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Madhu","family":"Ramesh","sequence":"first","affiliation":[{"name":"Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur P.O., Bengaluru 560064, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thimmaiah","family":"Govindaraju","sequence":"additional","affiliation":[{"name":"Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur P.O., Bengaluru 560064, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041200394967000_2025.03.24.644978v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69113-7"},{"key":"2026041200394967000_2025.03.24.644978v1.2","doi-asserted-by":"crossref","unstructured":"Knopman D.S. , Amieva H. , Petersen R. 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