Machine learning-guided Huanglian Jiedu decoction targets STING in periodontitis-induced Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder increasingly associated with peripheral inflammatory conditions such as chronic periodontitis (CP); however, the molecular mechanisms linking these conditions remain poorly understood. Here, we investigated the therapeutic effects of Huanglian Jieddu Decoction (HLJDD) on CP-induced AD using an integrative machine learning-guided multi-omics approach. Analysis of public single-cell RNA-sequencing data revealed pronounced inflammatory activation in microglia from AD samples. We further established a CP-induced AD rat model and performed hippocampal transcriptomic profiling. Multiple complementary machine learning strategies, including Random Forest-based feature selection, support vector machine-based refinement, network modeling, and interpretable model analysis, were applied to prioritize disease-relevant pathways from high-dimensional transcriptomic data. Across models, components of the cGAS-STING signaling pathway consistently exhibited strong and directional contributions to CP-AD pathology, indicating a central inflammatory axis linking peripheral infection to neurodegeneration. Guided by these data-driven insights, in vivo and in vitro experiments demonstrated that HLJDD suppressed cGAS-STING activation, attenuated neuroinflammation, and improved cognitive function in CP-induced AD models. Collectively, this study highlights the value of machine learning-assisted transcriptomic interpretation for mechanistic prioritization and identifies HLJDD as a multitarget therapeutic strategy for CP-induced AD.