Mechanistic Insights into Active Components of Rosa Roxburghii Juice Against Fluoride-Induced Osteoarthritis.

Fluoride-induced osteoarthritis (F-OA) is a debilitating manifestation of endemic fluorosis, with limited preventive or therapeutic strategies. Rosa roxburghii juice (RRJ), a traditional medicinal/edible product, has shown protective effects against skeletal fluorosis, yet its active constituents and molecular mechanisms are not fully understood. In this study, an integrated strategy combining bioinformatics analysis, network pharmacology, molecular docking and dynamics simulations, limited proteolysis-mass spectrometry (LiP-MS), and in vitro experiments was employed to systematically elucidate the protective mechanisms of RRJ against F-OA. Forty-four core F-OA-associated genes were identified, with TP53 and the p53 signaling pathway emerging as central regulatory hubs. Quercetin, Epicatechin, Emodin, and Ellagic acid were screened as key bioactive components of RRJ and demonstrated strong binding affinity toward core targets, including TP53. Cellular experiments showed that these compounds significantly attenuated sodium fluoride-induced cellular injury. LiP-MS analysis further revealed widespread protein conformational remodeling following treatment, with TP53 exhibiting pronounced structural sensitivity. Mechanistically, these active compounds mitigated fluoride-induced pathological changes by suppressing p53 mRNA expression and restoring proteasome-mediated p53 degradation. This study provides systematic pharmacological evidence supporting Rosa roxburghii fruit as a promising functional food for the prevention and management of skeletal fluorosis and F-OA.