Exploring the Molecular Mechanisms of Fisetin in Treating Periodontitis Through Multiomics and Network Pharmacology.

BACKGROUND: Periodontitis (PD) is a common chronic inflammatory oral disease that severely affects patients' quality of life. Fisetin has been shown to possess antioxidant and anti-inflammatory properties in various biological systems. METHODS: This study first identified the molecular targets of fisetin for PD through network pharmacology analysis. The therapeutic effects of fisetin were then evaluated in an animal model of PD and validated through in vitro experiments. Additionally, we utilised single-cell and spatial transcriptomics technologies to identify key cell populations in PD and their spatial distribution. RESULTS: The study demonstrated that fisetin significantly reduced alveolar bone destruction in the rat model of PD. Single-cell transcriptomics revealed that fisetin primarily affects fibroblast populations. In vitro experiments showed that fisetin alleviated the cytotoxicity caused by high oxidative stress levels in human periodontal ligament fibroblasts (PDLFs) . CONCLUSION: Fisetin inhibits the progression of periodontitis by reducing oxidative stress levels in fibroblast populations. These findings support the potential of fisetin as a therapeutic agent for periodontitis and provide a scientific basis for future clinical trials and treatment strategies. CLINICAL RELEVANCE: By significantly reducing alveolar bone destruction and modulating fibroblast function, fisetin presents a novel therapeutic strategy for managing periodontitis. These results provide a scientific foundation for the design of clinical trials aimed at evaluating the efficacy of fisetin in PD patients. If validated in clinical settings, fisetin could be incorporated into treatment regimens, offering a pharmacological option that complements conventional periodontal therapies, thereby improving patient outcomes and quality of life.