Network Pharmacology-Guided Discovery of Fungal Autophagy Modulators for Tauopathies: Structural and Proteomic Evidence

Impaired autophagic clearance of hyperphosphorylated tau in tauopathies drives progressive accumulation of toxic tau species. This study examined fungal metabolites from Lion's Mane (Hericium erinaceus), Magic Mushrooms (Psilocybe spp.), and Ergot fungi (Claviceps spp.) as an untapped source of neuroactive compounds, using a computational workflow assessing structural diversity, blood-brain barrier permeability, and toxicity, combined with network pharmacology and protein-protein interaction analysis to identify autophagy-related targets. PPARG, GSK3B, and CSNK2A1 emerged as top candidates due to their complementary links between autophagy and tau pathology. Docking, MM/GBSA, molecular dynamics, and QSAR modelling confirmed stable, target-specific binding for Corallocin A and Erinacerin M (PPARG), Chaetopyranin and Ergocryptine (GSK3B), and Hericioic Acid D and Isohericerin (CSNK2A1), alongside Emodin, a reference compound active on all three targets; QSAR was informative only for PPARG candidates. Reanalysis of an independent hippocampal proteomic dataset from Alzheimer's patients showed significantly altered CSNK2A1 in the CA3 subfield, offering correlative support, while PPARG and GSK3B showed no significant changes, not precluding functional involvement. Overall, these findings identify fungal metabolites as promising multi-target autophagy modulators and provide a systematic strategy for prioritising candidates for experimental validation in tauopathies.