TRIM62 promotes osteoarthritis progression by facilitating GPX4 ubiquitination and chondrocyte ferroptosis

Objectives: This study investigates the role of Tripartite motif containing 62 (TRIM62) in osteoarthritis (OA) progression, focusing on its regulation of Glutathione Peroxidase 4 (GPX4) ubiquitination and chondrocyte Ferroptosis.

Methods: An OA rat model was established via anterior cruciate ligament transection (ACLT) and then primary chondrocytes were stimulated with interleukin-1β (IL-1β) in vitro. TRIM62 expression was manipulated using short hairpin RNA (shRNA) or overexpression plasmids. Ferroptosis was assessed by measuring GPX4, solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), Reactive Oxygen Species (ROS), ferrous iron (Fe²⁺), and mitochondrial membrane potential. Protein interactions were evaluated by co-immunoprecipitation (Co-IP).

Results: RIM62 expression was significantly increased in osteoarthritic cartilage and in chondrocytes treated with IL-1β. TRIM62 knockdown restored GPX4 and Collagen type II (COL II) expression, reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) levels, suppressed Ferroptosis, and alleviated cartilage damage in vivo. Conversely, TRIM62 overexpression exacerbated chondrocyte injury and Ferroptosis, effects specifically reversed by ferrostatin-1 (Fer-1). Mechanistically, TRIM62 directly interacted with GPX4 and promoted its proteasomal degradation.

Conclusions: TRIM62 facilitates OA progression by inducing GPX4 ubiquitination and degradation, thereby promoting chondrocyte Ferroptosis. The TRIM62-GPX4-ferroptosis axis represents a promising therapeutic target for OA.