DJ-1 promotes necroptosis of chondrocytes by the PTEN/PI3K-AKT signaling pathway.

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive cartilage degradation. Necroptosis has been recognized as a process closely associated with OA progression; however, its precise underlying mechanisms remain elusive. In this study, we found that the expression levels of DJ-1 and p-MLKL were significantly elevated in human OA cartilage tissue. Transmission electron microscopy revealed typical necroptotic morphology in OA chondrocytes. In vitro experiments demonstrated that DJ-1 overexpression exacerbated TSZ + LPS-induced chondrocyte necroptosis and disrupted extracellular matrix (ECM) metabolism. The PI3K/AKT signaling pathway can be involved in TNF-mediated necroptosis, while PTEN, as a negative regulator, inhibits the activation of this pathway primarily by dephosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Co-immunoprecipitation (Co-IP) assays showed that DJ-1 directly binds to and inhibits PTEN, thereby relieving its suppression of the PI3K/AKT signaling pathway. Treatment with the PI3K inhibitor LY294002 significantly alleviated DJ-1-induced chondrocyte necroptosis and ECM dysregulation. Furthermore, in vivo studies confirmed that DJ-1 knockdown attenuated DMM-induced OA progression and improved cartilage and subchondral bone structure. Collectively, these findings indicate that DJ-1 promotes chondrocyte necroptosis and ECM degradation through regulation of the PTEN/PI3K/AKT signaling pathway, thereby accelerating the onset and progression of OA. This may provide a new therapeutic target for the treatment of OA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-026-06122-3.