Acacetin targets STING to alleviate the destabilization of the medial meniscus induced osteoarthritis in mice

Abstract Osteoarthritis (OA), a widespread joint disorder affecting approximately 7% of the global population, is primarily characterized by the gradual loss of articular cartilage. This degeneration results from local inflammation, matrix depletion, and direct cartilage damage. A critical element in this cascade is the activation of the Stimulator of the Interferon Genes (STING) pathway. Emerging evidence underscores its potential as a therapeutic target, with natural products showing promise as inhibitors. This study centers on Acacetin, a basic unit of polyketides known for its anti-inflammatory attributes. Prior research has highlighted its potential interaction with STING based on the structure. Therefore, this study aimed to assess Acacetin's effectiveness as a STING inhibitor and its protective role against OA. In vitro experiments demonstrated that Acacetin pretreatment not only mitigated interleukin-1β (IL-1β)-induced cytotoxicity but also decreased the inflammatory response and degeneration in IL-1β-stimulated chondrocytes. In vivo studies revealed that Acacetin administration significantly reduced articular cartilage destruction, abnormal bone remodeling, and osteophyte formation in a model of OA induced by destabilization of the medial meniscus (DMM). Mechanistically, Acacetin was found to directly interact with STING, and inhibit IL-1β-induced activation of STING and subsequent phosphorylation of the TBK1/NFκB pathway in chondrocytes. In conclusion, our findings confirm that Acacetin is an effective inhibitor of STING, offering protection to chondrocytes against IL-1β-induced damage and attenuating the progression of OA in mice.