Yizhi Dihuang Decoction Ameliorates Mild Cognitive Impairment by Restoring Autophagy via PI3K-AKT-mTOR Modulation: In Vivo Validation and Network Pharmacology Analysis.

Mild cognitive impairment (MCI) lacks approved disease-modifying therapies. Classical multicomponent prescriptions may act on convergent neurobiological nodes. We combined network pharmacology with in vivo testing to evaluate Yizhi Dihuang Decoction (YZDHD). Constituents were curated from traditional chinese medicine systems pharmacology database and analysis platform (TCMSP) and high-throughput experiment- and reference-guided database of Traditional Chinese Medicine (HERB under blood-brain barrier-aware SwissADME criteria. Targets were inferred, intersected with MCI genes, organized into STRING and MCODE networks, and examined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment. Structure-based docking evaluated ligand-protein interactions across network-identified hub targets and ranked complexes by predicted binding energy. Predictions were tested in a D-galactose mouse model using the Morris water maze and novel object recognition, hippocampal histology with hematoxylin and eosin and Nissl staining, transmission electron microscopy, and molecular readouts by Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR), including PI3K, p-AKT/AKT, p-mTOR/mTOR, LC3-II/LC3-I, and p62/SQSTM1. We identified 152 bioavailable compounds and 381 overlapping targets that converged on hub kinases including AKT1, PIK3CA, PIK3CD, and mTOR; docking supported feasible engagement. In vivo, YZDHD improved spatial learning and recognition memory, preserved hippocampal cytoarchitecture and mitochondrial integrity, increased LC3-II/LC3-I, decreased p62/SQSTM1, and reduced activation indices of AKT and mTOR. YZDHD ameliorates MCI-like deficits by rebalancing PI3K-AKT-mTOR signaling and restoring autophagy-related activity. Signals for mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1 (HIF-1), epidermal growth factor receptor (EGFR), and toll-like receptor 4 (TLR4) broaden the mechanistic hypothesis space and warrant targeted follow-up.