Baicalein alleviates Alzheimer's disease pathology in AD models by activating the PI3K/AKT/GSK3β pathway to inhibit neuronal apoptosis.

UNLABELLED: Baicalein, a bioactive flavonoid from Scutellaria baicalensis, exhibits anti - inflammatory, antioxidant, and neuroprotective properties. Its potential for Alzheimer’s disease (AD) therapy is emerging. This study evaluated its therapeutic efficacy and molecular mechanisms using APP/PS1 transgenic mice and SH - SY5Y - APP/PS1 cells. Morris water maze and novel object recognition tests assessed cognitive deficits in mice. Hippocampal pathology and neuronal apoptosis were examined via Nissl staining, transmission electron microscopy, and TUNEL assay. For SH - SY5Y - APP/PS1 cells, CCK − 8 optimized drug concentrations, while Annexin V - FITC/PI measured apoptosis and ELISA analyzed Aβ1–42. Network pharmacology identified PI3K/AKT as a key target. Baicalein improved cognition, reduced hippocampal neurodegeneration, decreased neuronal apoptosis, and lowered Aβ1–42 accumulation. It activated the PI3K/AKT pathway, increasing p - PI3K/p - AKT/BCL2 and decreasing p - GSK3β/Caspase − 3. These findings demonstrate that baicalein ameliorates AD by inhibiting neuronal apoptosis via the PI3K/AKT/GSK3β cascade, validating its potential as an AD therapeutic agent. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-47003-w.