Exploring the Neuroprotective Effects of Walnut (Juglans regia L.) Against Cognitive Impairment in Alzheimer's Disease Through the MAPK-mTORC1-TFEB-Mediated Endolysosomal Pathway: A Network Pharmacology and Molecular Docking Approach.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis. Given the clinical need for multi-target interventions, this study elucidated the neuroprotective mechanisms of walnut (Juglans regia L.) against AD-related cognitive impairment.

Methods

We characterized 25 bioactive constituents (fatty acids and ellagitannins) and constructed a protein-protein interaction (PPI) network. GO/KEGG enrichment, integrated with Ingenuity Pathway Analysis (IPA), deciphered pharmacological pathways, followed by molecular docking to evaluate ligand-target binding thermodynamics. Network analysis revealed that walnut phytochemicals synergistically modulate the MAPK-mTORC1-TFEB-mediated endolysosomal homeostasis pathway. Molecular docking indicated that ellagitannins (strictinin, pedunculagin, tellimagrandin I) exhibit robust affinities for upstream RAS/RAF/MEK kinases, suppressing pro-pathogenic signaling. Concurrently, gallic acid targeted ABCA1 and TFEB, promoting TFEB activation and nuclear translocation to enhance beta-amyloid clearance and lysosomal biogenesis. This study provides evidence that walnut attenuates AD pathology through "multi-component" reinforcement of the endolysosomal defense system, establishing a mechanistic foundation for walnut as a promising functional food.