GPx6 downregulation drives ferroptosis in Kashin-Beck disease chondrocytes via the SLC7A11/GPx4 axis.

Kashin-Beck disease (KBD) is an endemic osteoarthropathy characterized by chondrocyte death and extracellular matrix (ECM) degradation; however, the underlying molecular mechanisms remain poorly understood. This study aimed to explore whether glutathione peroxidase 6 (GPx6) is involved in regulating ferroptosis and matrix degradation in KBD cartilage injury. In articular cartilage from children with KBD, GPx6 expression was markedly reduced, particularly in the deep zone where chondrocyte death and matrix loss were most severe. Similarly, downregulation of GPx6 was observed in a T-2 toxin‑induced rat model and in C28/I2 chondrocytes, accompanied by decreased COL2A1 and ACAN levels and increased expression of MMP13 and ADAMTS4. Molecular docking indicates a potential interaction between T-2 toxin and GPx6. Gpx6 knockout mice exhibited signs of ECM degradation in articular cartilage, along with an enhanced susceptibility to T-2 toxin exposure. Mechanistically, Gpx6 deficiency led to elevated MDA levels, reduced SOD activity and GSH/GSSG ratio, as well as mitochondrial shrinkage, cristae loss, and lipid peroxidation. Knockdown of GPX6 suppressed the expression of SLC7A11, SLC3A2, and GPx4, while Ferrostatin‑1 partially reversed these ferroptosis‑related alterations but failed to restore GPx6 expression. Conversely, overexpression of GPX6 partially restored the function of the SLC7A11/GPx4 axis, improved redox balance, attenuated mitochondrial lipid peroxidation, and mitigated matrix degradation. Collectively, these findings suggest that downregulation of GPx6 may be closely associated with ferroptosis in KBD chondrocytes, and that GPx6 may serve as a potential upstream regulator of this process. Furthermore, dysregulation of the GPx6‑SLC7A11/GPx4 pathway may also be involved in the pathological process of cartilage injury in KBD.