TRIM62 promotes osteoarthritis progression by facilitating GPX4 ubiquitination and chondrocyte ferroptosis

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.

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).

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.

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.