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.