Abstract

Background Facet joint osteoarthritis (FJOA) is increasingly recognized as a key pathological contributor to low back pain, but effective treatment strategies remain elusive. Asperosaponin VI (ASA VI) exhibits significant anti-inflammatory effects and promotes mitophagy. However, the mechanism of ASA VI's action in FJOA remains unclear. Objective: This study explores ASA VI's impact on mitophagy and cellular pyroptosis in FJOA chondrocytes and elucidates the underlying mechanisms. Methods: The therapeutic mechanism of ASA VI in FJOA was initially investigated through network pharmacology analysis. A rat model of FJOA and an IL-1β-induced chondrocyte model to assess the protective effects of ASA VI on lumbar facet joint (LFJ) cartilage. Additionally, untargeted metabolomics and cellular transcriptomics analyses were performed to assess the roles of ASA VI in FJOA. Results: Network pharmacology identified a strong link between ASA VI's effects and mitophagy. In vivo and in vitro tests confirmed ASA VI's biocompatibility, facilitated subchondral bone and cartilage extracellular matrix (ECM) remodeling, and delayed FJOA progression. Untargeted metabolomics indicated that ASA VI modulated the metabolic environment in FJOA by reducing excess metabolites, enhancing tricarboxylic acid (TCA) cycle activity, and promoting mitophagy. Mechanistically, ASA VI activated the PINK1/Parkin pathway, restoring mitochondrial function and autophagy in chondrocytes. Further experiments confirmed that ASA VI induces mitophagy via the PINK1/Parkin pathway, inhibits the cGAS/STING pathway, and reduces chondrocyte pyroptosis. Conclusions: ASA VI induces mitophagy in chondrocytes via the PINK1/Parkin pathway, suppresses the cGAS/STING signaling pathway, and reduces chondrocyte pyroptosis, thereby slowing FJOA progression. ASA VI consequently represents a promising treatment option for F