Affiliation:
1. School of Medicine, Shanghai University
2. Institute of Translational Medicine, Shanghai University
3. First Affiliated Hospital of Wenzhou Medical University
4. Affiliated Stomatological Hospital of Nanjing Medical University
Abstract
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.
Publisher
Research Square Platform LLC
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