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Here, we identify isocitrate dehydrogenase 1 (IDH1), a key enzyme in the TCA cycle, as a critical pathogenic driver of AD in microglia. IDH1 expression was markedly upregulated in microglia from both AD patients and 5\u00d7FAD mice. Elevated IDH1 promoted excessive cytosolic citrate consumption, which restricted citrate shuttling into mitochondria and impaired mitochondrial TCA cycle function. This citrate metabolic imbalance further disrupted epigenetic regulation, thereby exacerbating AD\u2010related pathological processes. Using structure\u2010based screening and co\u2010crystallization analysis, we identified Kinsenoside (KIN), a natural small molecule, as a selective competitive inhibitor of IDH1 that binds to its isocitrate\u2010binding pocket. Targeting IDH1 with KIN inhibited its activity, which restored intracellular citrate distribution, reactivated mitochondrial TCA cycle flux, and reestablished metabolic homeostasis. Notably, this intervention not only attenuated neuroinflammation but also reduced \u03b2\u2010amyloid (A\u03b2) deposition and significantly improved cognitive performance in 5\u00d7FAD mice. Collectively, our findings establish IDH1\u2010mediated metabolic dysregulation as a pivotal pathogenic mechanism in AD and highlight KIN as a promising therapeutic candidate by targeting microglial IDH1 to restore metabolic and functional homeostasis.<\/jats:p>","DOI":"10.1002\/advs.75125","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T19:15:47Z","timestamp":1776194147000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Kinsenoside Targets IDH1 to Restore Microglial Immune\u2010Metabolic Homeostasis for Alzheimer's Disease Therapy"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1840-1203","authenticated-orcid":false,"given":"Qianqian","family":"Li","sequence":"first","affiliation":[{"name":"The Brain Science Center Beijing Institute of Basic Medical Sciences  Beijing 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Greater Bay Area Center for Brain Science and Brain\u2010Inspired Intelligence Guangdong\u2010Hong Kong Joint Laboratory for Psychiatric Disorders Guangdong Province Key Laboratory of Psychiatric Disorders Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases Department of Neurobiology School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Life Sciences Beijing University of Chinese Medicine  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3499-2717","authenticated-orcid":false,"given":"Shuoshuo","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences Beijing University of Chinese Medicine  Beijing 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