Integrated Network Pharmacology, Molecular Docking, and Experimental Validation Elucidating the Therapeutic Mechanism of Idesia polycarpa Crude Oil in Aluminum Chloride‐Induced Alzheimer's Rat Models

While mounting evidence points to a potential link between industrial aluminum exposure and neurodegenerative diseases like Alzheimer's disease (AD), the precise intervention strategies remain an area of active research. This study proposes a “multi‐target synergy and dose threshold control” exploratory framework for evaluating Idesia polycarpa crude oil (IPCO) in an aluminum‐induced AD model. An integrated analytical approach employing GC–MS and network pharmacology was used to identify three candidate core components—(Z,Z)‐9,12‐octadecadienoic acid, Beta‐amyrin, and 2,4‐di‐tert‐butylphenol—that were computationally predicted to influence a network of 35  ad ‐related pathways (e.g., Calcium and PPAR signaling) via eight potential key targets (including PTGS2 , PPARG , and AKT1 ). In vivo experiments revealed a dose‐dependent modulation of AD‐related pathology following IPCO intervention. The high‐dose group showed the most marked improvements in several therapeutic markers, including reduced aluminum load, an anti‐inflammatory shift in cytokine levels (elevated IL‐10, decreased IL‐4, IL‐6, IL‐1β, and TNF‐α), and remodeling of the gut microbiota characterized by an increase in putative short‐chain fatty acid (SCFA)‐producing genera such as the [Eubacterium]‐xylanophilum‐group and NK4A214‐group ( Firmicutes ). Paradoxically, this same high dose was associated with a decline in spatial cognitive performance. This biphasic effect may be preliminarily explained by a dual microbial mechanism: the inhibition of the pro‐inflammatory associated [Eubacterium]‐oxidoreducens‐group alongside the expansion of taxa linked to a neuroprotective SCFA metabolic network. As one of the first studies to map these multi‐dimensional “constituent–microbiota–neuroinflammation” interactions for IPCO, our findings highlight its complex, dose‐sensitive bioactivity. Importantly, they underscore the critical need for subsequent pharmacokinetic and direct target engagement studies. Step 1: Component identification and target screening: The chemical composition of IPCO was characterized using GC–MS, identifying two major fatty acids and six fat‐soluble active substances. A total of 149 potential drug targets were predicted via Pharm Mapper and SwissTargetPrediction. Concurrently, 2029 genes associated with Alzheimer's Disease (AD) were retrieved from the OMIM, TTD, and GeneCards databases. Through the intersection analysis of “ingredient‐target‐disease,” combined with STRING‐based Protein–Protein Interaction (PPI) analysis, Gene Ontology (GO), and KEGG pathway enrichment, the molecular mechanisms underlying the neuroprotective effects of IPCO were elucidated. Step 2: Structural validation (molecular docking): Molecular docking simulations were performed to evaluate the binding affinity between active ingredients and core targets. The results demonstrated that the core component, β‐amyrin, exhibited high binding affinity with key protein targets. Specifically, the binding energies of β‐amyrin with PPARG and ERBB2 were −8.80 and −9.10 kcal/mol, respectively. These high‐affinity interactions provide structural evidence validating the predictions made through network pharmacology. Step 3: In vivo verification (gut microbiota and biochemical markers): In vivo experiments confirmed that IPCO intervention significantly modulated the gut microbiota in AD rats, notably increasing the abundance of the [Eubacterium]‐oxidoreducens‐group . Biochemically, IPCO treatment markedly enhanced the levels of SCFAs and the anti‐inflammatory cytokine IL‐10. Furthermore, a significant reduction in hippocampal Al accumulation and inhibition of AChE activity were observed. These findings suggest that IPCO exerts its anti‐AD effects potentially by modulating the gut‐microbiota‐brain axis and improving cholinergic system function. This study systematically elucidated the neuroprotective mechanisms of IPCO against AD through an integrated approach of network pharmacology, molecular docking, and in vivo experiments. Initially, eight core active ingredients were identified in IPCO via GC–MS, with 149 potential targets and 2029  ad ‐related genes mapped through multi‐database screening. Molecular docking further validated that the core component, β‐amyrin, exhibited high binding affinities for key targets including PPARG (−8.80 kcal/mol) and ERBB2 (−9.10 kcal/mol). Finally, in vivo verification demonstrated that IPCO intervention significantly modulated the gut‐microbiota‐brain axis by increasing the abundance of the [Eubacterium]‐oxidoreducens‐group , elevating levels of SCFAs and IL‐10, while concurrently reducing hippocampal Al accumulation and inhibiting AChE activity.