Epimedium attenuates neuroinflammation and ameliorates Alzheimer's disease through a KAT2B-dependent mechanism

Background Alzheimer's disease (AD) is the leading cause of dementia worldwide, yet effective therapies for this neurodegenerative disorder remain scarce. Epimedium , a herb with a history of thousands of years in traditional Chinese medicine, exhibits diverse biological activities and holds potential therapeutic effects against Alzheimer's disease. However, studies on its modern pharmacological mechanisms remain relatively limited. Methods TCMSP and PubChem were used to retrieve Epimedium constituents, and SwissTargetPrediction was used to predict potential targets. GeneCards, OMIM, and GEO databases were used to identify targets associated with AD. The AD model was established by intragastric administration of AlCl3 combined with intraperitoneal injection of D-galactose, with the normal saline group serving as controls. Cognitive function was assessed by the Morris water maze, and histopathological changes were observed by H&E staining. ELISA detected IL-1β and TNF-α levels, and qRT-PCR detected KAT2B, NF-κB, IL-1β, and TNF-α expression. Results We identified 172 key targets, with KAT2B and ACACB determined as core genes through transcriptomic screening. In vivo studies showed that Epimedium significantly ameliorated cognitive deficits and alleviated histopathological damage in hippocampal neurons. Furthermore, Epimedium suppressed neuroinflammation by reducing IL-1β and TNF-α levels and modulated the mRNA expression of key targets (KAT2B, NF-κB) in the hippocampus. Conclusion Epimedium improves pathological alterations in the hippocampal tissue and alleviates cognitive and behavioral impairments in rats by modulating neuroinflammation through KAT2B, thereby providing a scientific basis for its potential application and development as a therapeutic agent.