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MicroRNAs (miRNAs) are crucial regulators of these pathological processes. We employed transcriptomic analysis in an APP\/PSEN1 Tg AD mouse model to identify dysregulated miRNAs and construct a miRNA\u2013mRNA\u00a0pathway network. We discovered increased miR-7a expression in the AD brain, targeting Kr\u00fcppel-like factor 4 (Klf4), a transcriptional factor implicated in amyloid-\u03b2 (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\u2013Klf4 axis with blood\u2013brain\u00a0barrier (BBB)-permeable compound effectively mitigates neuroinflammation and ferroptosis, suggesting the miR-7a\u2013Klf4 axis as a novel therapeutic target for AD.<\/jats:p>","DOI":"10.1093\/narmme\/ugaf022","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T07:29:07Z","timestamp":1751268547000},"source":"Crossref","is-referenced-by-count":12,"title":["MiR-7a\u2013Klf4 axis as a regulator and therapeutic target of neuroinflammation and ferroptosis in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"2","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\u00a0560064\u00a0 Karnataka ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9423-4275","authenticated-orcid":false,"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\u00a0560064\u00a0 Karnataka ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"2025071105563056800_B1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/S0140-6736(06)69113-7","article-title":"Alzheimer\u2019s disease","volume":"368","author":"Blennow","year":"2006","journal-title":"The Lancet"},{"key":"2025071105563056800_B2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer 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