Skullcapflavone II alleviates osteoarthritis by inhibiting inflammation and ferroptosis via the SLC7A11/GPX4 signaling pathway

Abstract

Abstract Osteoarthritis (OA), the most prevalent degenerative joint disease, leads to significant disability in the elderly and is characterized by functional and structural deterioration of the knee joint. This study aimed to investigate the therapeutic potential of skullcapflavone II (SkII), a flavonoid known for its anti-inflammatory properties, in the context of OA. Our results demonstrated that SkII markedly suppressed IL-1β–induced extracellular matrix degradation and apoptosis in chondrocytes. Furthermore, SkII reduced reactive oxygen species and malondialdehyde levels while enhancing superoxide dismutase activity and the glutathione/glutathione disulfide ratio. SkII also upregulated the expression of SLC7A11 and glutathione peroxidase 4 (GPX4). Mechanistic investigations revealed that SkII, similar to the ferroptosis inhibitor ferrostatin-1, effectively counteracted erastin-induced apoptosis and extracellular matrix degradation. Both SkII and ferrostatin-1 promoted SLC7A11 and GPX4 expression at transcriptional and protein levels and diminished ferrous ion (Fe2+) accumulation in chondrocytes. In vivo experiments confirmed that SkII treatment attenuated ferroptosis in OA rats by activating the SLC7A11/GPX4 pathway. In conclusion, our findings indicate that SkII alleviates OA progression by inhibiting ferroptosis through the SLC7A11/GPX4 signaling axis. These results underscore the potential of SkII as a promising therapeutic candidate for the treatment and prevention of OA.