RICTOR-mediated GPX4 downregulation regulates chondrocyte ferroptosis in osteoarthritis progression.

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease worldwide and the leading cause of chronic pain and mobility limitation in the elderly. Numerous studies have demonstrated that ferroptosis plays a crucial role in the development and progression of OA; however, the precise mechanisms remain to be elucidated. RICTOR (Rapamycin-Insensitive Companion of mTOR) is a key protein in cellular signal transduction and an essential component of mTORC2 (mammalian target of rapamycin complex 2), vital for the stability and activity of the complex. Our previous work established that RICTOR regulates autophagy to influence OA, yet whether RICTOR affects ferroptosis is unclear. This study aims to investigate the role of RICTOR in chondrocyte ferroptosis and to explore the RICTOR-ferroptosis axis as a potential therapeutic target.First, we observed elevated RICTOR expression in cartilage from OA patients and destabilization of the medial meniscus (DMM) mice, as well as in erastin-treated OA chondrocytes. RICTOR knockdown attenuated erastin-induced reduction of Col2a1 and promoted down-regulation of MMP13. Moreover, the RICTOR inhibitor JR-AB2 ameliorated cartilage degradation in the DMM-induced OA mouse model and mitigated the decline of GPX4 in vivo. Overall, our results indicate that RICTOR induces ferroptosis in OA by regulating GPX4 expression.