Abstract

Periodontitis is a chronic inflammatory disease; its persistent inflammatory cascade leads to destruction of periodontal tissues and alveolar bone resorption. Isorhapontigenin (ISO) is an orally available dietary polyphenol. As a resveratrol analog, it exhibits stronger anti-inflammatory activity, yet its functional role and molecular mechanisms in periodontitis remain unclear. This study investigated the anti-inflammatory effects of ISO on periodontitis and its potential molecular mechanisms using a rat periodontitis model and lipopolysaccharide (LPS)-induced human gingival fibroblasts (HGFs) cell model. ISO effectively reduced inflammatory infiltration in gingival tissue while promoting alveolar bone repair and tissue remodeling. Integrated network pharmacology and bioinformatics analysis suggested the EGFR/PI3K/AKT signaling pathway as a potential key target. Mechanistic studies demonstrated that ISO inhibits LPS-mediated phosphorylation of EGFR and its downstream PI3K/AKT in HGFs, thereby blocking inflammatory signaling. In vivo, ISO significantly downregulated the expression of proteins in the EGFR/PI3K/AKT pathway and related inflammatory factors. In summary, this work confirmed for the first time that ISO significantly reduces inflammatory responses and tissue destruction in periodontitis, at least in part, by regulating the EGFR/PI3K/AKT pathway, providing both experimental and theoretical support for its development as an adjunctive anti-inflammatory drug for periodontal disease.