Forsythoside A mitigates osteoarthritis and inhibits chondrocyte senescence by promoting mitophagy and suppressing NLRP3 inflammasome via the Nrf2 pathway

BACKGROUND: Chondrocyte senescence and inflammation are hallmarks of osteoarthritis (OA). Forsythiaside A (FTA), a phenylethanol glycoside isolated from air-dried fruits of Forsythia, has been reported to have significant anti-inflammatory and antioxidant properties. However, its protective effects against OA have not been elucidated. PURPOSE: We explored the therapeutic efficacy of FTA in inhibiting chondrocyte senescence and inflammation during OA, as well as the potential underlying mechanisms. STUDY DESIGN: This study aimed to investigate the novel mechanism of FTA in alleviating OA in both cell and animal models. METHODS: The protective effect of FTA against tert‑butyl hydroperoxide-induced chondrocyte damage was assessed, and the effects of FTA on cartilage aging and OA progression were evaluated using a medial meniscus (DMM)-induced knee OA mouse model. The regulatory effects of FTA on the NLRP3 Inflammasome, mitophagy, and the PKC/Nrf2 pathway were also explored. RESULTS: In vitro, FTA improved mitochondrial function, enhanced mitophagy, suppressed NLRP3 inflammasome activation, and inhibited chondrocyte senescence; however, these chondroprotective effects were partially reversed after mitophagy inhibition, NLRP3 inflammasome activation, and Nrf2 pathway inhibition. Furthermore, we found that FTA directly interacts with Nrf2 and enhances its phosphorylation by protein kinase C (PKC). In vivo, FTA attenuated the pathological signs of knee OA in a DMM-model mouse model, which was partially reversed by ML385. CONCLUSION: FTA inhibited chondrocyte senescence and OA progression by activating the PKC-Nrf2 pathway. Thus, FTA is a potential novel therapeutic agent for OA.