TRIM8 enhances chondrocyte ferroptosis by inhibiting YTHDF2-m6A mediated SREBF2 mRNA degradation to promote OA progression.

Chondrocyte ferroptosis plays a crucial role in osteoarthritis (OA) progression. Our previous study demonstrated that TRIM8 knockdown alleviated IL-1β-induced chondrocyte injury. However, the involvement of TRIM8 in regulating OA progression through ferroptosis remains unclear. In this study, human OA and normal cartilage samples were collected to examine ferroptosis and TRIM8 expression. We found that both ferroptosis markers and TRIM8 protein levels were elevated in OA cartilage compared to controls. An OA cell model was established by stimulating chondrocytes with IL-1β. TRIM8 knockdown mitigated IL-1β-induced ferroptosis, extracellular matrix (ECM) degradation, and inflammation in chondrocytes. Mechanistically, TRIM8 facilitated the ubiquitylation of YTHDF2 via its RING domain, promoting YTHDF2 protein degradation. This inhibited YTHDF2-m6A-induced SREBF2 mRNA degradation, thereby upregulating SREBF2 expression and enhancing chondrocyte ferroptosis. As expected, SREBF2 overexpression reversed the protective effect of TRIM8 silencing on IL-1β-induced chondrocyte injury. An OA mouse model was established using destabilized medial meniscus surgery, and TRIM8 deficiency alleviated cartilage degradation and synovial inflammation. In conclusion, TRIM8 promotes chondrocyte ferroptosis by suppressing YTHDF2-m6A mediated SREBF2 mRNA degradation, thereby accelerating OA progression.