Abstract
BACKGROUND: Periodontitis is a persistent inflammatory disease caused by the interplay between periodontal pathogens and the host immune response, leading not only to inflammatory infiltration of periodontal tissues but also to resorption and destruction of alveolar bone. Ginsenoside Rg1, a major pharmacologically active constituent of ginseng, exhibits anti-inflammatory, osteogenic, and immunomodulatory properties. This study investigated the therapeutic potential of Rg1 in an experimental periodontitis model in rats and explored its underlying molecular mechanisms. METHODS: An experimental periodontitis model was established in 8-week-old male Sprague-Dawley (SD) rats by ligating the maxillary first molars and inoculating with Porphyromonas gingivalis suspension. Micro-computed tomography (micro-CT) and hematoxylin–eosin (H&E) staining were used to evaluate inflammatory bone destruction. Tartrate-resistant acid phosphatase (TRAP) staining and immunofluorescence (IF) were performed to assess osteoclast numbers and osteogenic marker expression. Gene and protein expression levels of inflammatory cytokines and the immune receptor Toll-like receptor 2 (TLR2) were measured using RT-PCR and IF. Western blotting was conducted to evaluate the phosphorylation status of the PI3K/AKT signaling pathway. RESULTS: Rg1 at a dose of 500 µg/kg exhibited optimal pharmacological activity, effectively alleviating inflammatory damage and bone destruction in periodontitis rats. Rg1 treatment significantly decreased the expression of TLR2 and IL-1β, while increasing that of TGF-β1. Additionally, Rg1 upregulated the expression of osteogenic markers and inhibited osteoclast formation. Notably, co-treatment with PI3K/AKT pathway inhibitor LY294002 significantly reduced the protective effects of Rg1, suggesting that the PI3K/AKT pathway is indispensable for its protective effects. CONCLUSION: Ginsenoside Rg1 attenuates experimental periodontitis by regulating the PI3K/AKT signaling pathway and suppressing TLR2 expression. This study provides a novel reference for pharmacological mechanism and new drug development of Rg1 in the therapeutic applications of periodontitis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12903-026-07950-2.