Abstract

Osteoarthritis (OA) is a prevalent degenerative joint disorder marked by cartilage damage, synovitis, and impaired joint function, posing a substantial public health challenge globally. Establishing ideal models is essential for promoting the progress of OA treatment. Considering the confirmed association between ferroptosis and OA pathogenesis, as well as the lack of validated models for investigating ferroptosis in OA, this study assessed Erastin's potential as an inducer of OA-like degeneration. In vitro experiments showed that Erastin induced ferroptosis, senescence, inflammation, and extracellular matrix degradation in mouse, C28I2, and human chondrocytes, accompanied by NRF2 pathway activation. In cartilage explants from OA patients and normal mice, Erastin decreased COL2A1 expression and increased MMP13 levels. In vivo, a single intra-articular Erastin injection in mice led to obvious cartilage degeneration and synovitis; immunohistochemical results confirmed downregulated GPX4/COL2A1 and upregulated MMP13, consistent with the surgical DMM model. Our findings indicate that a single intra-articular Erastin injection can establish a stable, simplified OA model targeting ferroptosis pathways, providing a useful tool for precise mechanistic research and efficient preclinical testing of anti-ferroptosis therapies.