miR‑223‑3p promotes microglial lactylation and M1 polarization via the FBXW7/Notch1/Hes1/SIRT1 axis

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and is closely linked to microglial M1 polarization. In the present study, miR‑223‑3p was identified as a critical regulator of microglial metabolic reprogramming. Analyses of Gene Expression Omnibus and AD Neuroimaging Initiative datasets revealed significant upregulation of miR‑223‑3p in the brain, blood, and cerebrospinal fluid of patients with AD. The overexpression of miR‑223‑3p promoted M1 polarization and increased Reactive Oxygen Species (ROS) levels. Transcriptomic, metabolomic and Seahorse analyses revealed increased glycolysis, lactate production and lactylation, whereas inhibition of lactylation reduced M1 polarization and ROS accumulation. Mechanistically, miR‑223‑3p suppressed SIRT1 expression and directly targeted FBXW7, leading to activation of the Notch1/Hes1 pathway and further suppression of SIRT1. In summary, these findings demonstrate that miR‑223‑3p drives microglial lactylation‑mediated M1 polarization through the FBXW7/Notch1/Hes1/SIRT1 signaling axis. The present study provides new insight into the role of lactylation in neuroinflammation and highlights miR‑223‑3p as a potential therapeutic target for AD.